New indanyloxydihydrobenzofuranylacetic acids

ABSTRACT

The present invention relates to compounds of general formula I, 
     
       
         
         
             
             
         
       
     
     wherein the groups R 1 , R 2  and m are defined as in claim  1 , which have valuable pharmacological properties, in particular bind to the GPR40 receptor and modulate its activity. The compounds are suitable for treatment and prevention of diseases which can be influenced by this receptor, such as metabolic diseases, in particular diabetes type 2.

FIELD OF THE INVENTION

The present invention relates to novelindanyloxydihydrobenzofuranylacetic acids, that are agonists of theG-protein coupled receptor 40 (GPR40, also known as free fatty acidreceptor FFAR 1), to processes for their preparation, to pharmaceuticalcompositions containing these compounds and to their medical use for theprophylaxis and/or treatment of diseases which can be influenced by themodulation of the function of GPR40. Particularly, the pharmaceuticalcompositions of the invention are suitable for the prophylaxis and/ortherapy of metabolic diseases, such as diabetes, more specifically type2 diabetes mellitus, and conditions associated with the disease,including insulin resistance, obesity, cardiovascular disease anddyslipidemia.

BACKGROUND OF THE INVENTION

Metabolic diseases are diseases caused by an abnormal metabolic processand may either be congenital due to an inherited enzyme abnormality oracquired due to a disease of an endocrine organ or failure of ametabolically important organ such as the liver or the pancreas.

Diabetes mellitus is a disease state or process derived from multiplecausative factors and is defined as a chronic hyperglycemia associatedwith resulting damages to organs and dysfunctions of metabolicprocesses. Depending on its etiology, one differentiates between severalforms of diabetes, which are either due to an absolute (lacking ordecreased insulin secretion) or to a relative lack of insulin. Diabetesmellitus Type I (IDDM, insulin-dependent diabetes mellitus) generallyoccurs in adolescents under 20 years of age. It is assumed to be ofauto-immune etiology, leading to an insulitis with the subsequentdestruction of the beta cells of the islets of Langerhans which areresponsible for the insulin synthesis. In addition, in latent autoimmunediabetes in adults (LADA; Diabetes Care. 8: 1460-1467, 2001) beta cellsare being destroyed due to autoimmune attack. The amount of insulinproduced by the remaining pancreatic islet cells is too low, resultingin elevated blood glucose levels (hyperglycemia). Diabetes mellitus TypeII generally occurs at an older age. It is above all associated with aresistance to insulin in the liver and the skeletal muscles, but alsowith a defect of the islets of Langerhans. High blood glucose levels(and also high blood lipid levels) in turn lead to an impairment of betacell function and to an increase in beta cell apoptosis.

Persistent or inadequately controlled hyperglycemia is associated with awide range of pathologies. Diabetes is a very disabling disease, becausetoday's common anti-diabetic drugs do not control blood sugar levelswell enough to completely prevent the occurrence of high and low bloodsugar levels. Out of range blood sugar levels are toxic and causelong-term complications for example retinopathy, renopathy, neuropathyand peripheral vascular disease. There is also a host of relatedconditions, such as obesity, hypertension, stroke, heart disease andhyperlipidemia, for which persons with diabetes are substantially atrisk.

Obesity is associated with an increased risk of follow-up diseases suchas cardiovascular diseases, hypertension, diabetes, hyperlipidemia andan increased mortality. Diabetes (insulin resistance) and obesity arepart of the “metabolic syndrome” which is defined as the linkage betweenseveral diseases (also referred to as syndrome X, insulin-resistancesyndrome, or deadly quartet). These often occur in the same patients andare major risk factors for development of diabetes type II andcardiovascular disease. It has been suggested that the control of lipidlevels and glucose levels is required to treat diabetes type II, heartdisease, and other occurrences of metabolic syndrome (see e.g., Diabetes48: 1836-1841, 1999; JAMA 288: 2209-2716, 2002).

The free fatty acid receptor GPR40 (also referred to as either FFAR,FFAR1, or FFA1) is a cell-surface receptor and a member of the genesuperfamily of G-protein coupled receptors, which was first identifiedas a so-called orphan receptor, i.e. a receptor without a known ligand,based on the predicted presence of seven putative transmembrane regionsin the corresponding protein (Sawzdargo et al. (1997) Biochem. Biophys.Res. Commun. 239: 543-547). GPR40 is found to be highly expressed inseveral particular cell types: the pancreatic β cells andinsulin-secreting cell lines, as well as in enteroendocrine cells, tastecells, and is reported to be expressed in immune cells, splenocytes, andin the human and monkey brain. Meanwhile, fatty acids of varying chainlengths are thought to represent the endogenous ligands for GPR40,activation of which is linked primarily to the modulation of the Gqfamily of intra-cellular signaling G proteins and concomitant inductionof elevated calcium levels, although activation of Gs- and Gi-proteinsto modulate intracellular levels of cAMP have also been reported. GPR40is activated especially by long-chain FFA, particularly oleate, as wellas the PPAR-gamma agonist rosiglitazone.

It has been recognized that the fatty acids that serve as activators forGPR40 augment the elevated plasma glucose-induced secretion of insulinthrough GPR40 receptors that are expressed in the insulin secretingcells (Itoh et al. (2003) Nature 422: 173-176; Briscoe et al. (2003) J.Biol. Chem. 278: 11303-11311; Kotarsky et al. (2003) Biochem. Biophys.Res. Commun. 301: 406-410). Despite initial controversy, the use ofGPR40 agonist appears to be the appropriate for increasing insulinrelease for the treatment of diabetes (see e.g. Diabetes 2008, 57, 2211;J. Med. Chem. 2007, 50, 2807). Typically, long term diabetes therapyleads to the gradual diminution of islet activity, so that afterextended periods of treatment Type 2 diabetic patients need treatmentwith daily insulin injections instead. GPR40 agonists may have thepotential to restore or preserve islet function, therefore, GPR40agonists may be beneficial also in that that they may delay or preventthe diminution and loss of islet function in a Type 2 diabetic patient.

It is well established that the incretins GLP-1 (glucagon-likepeptide-1) and GIP (glucose-dependent insulinotropic peptide; also knownas gastric inhibitory peptide) stimulate insulin secretion and arerapidly inactivated in vivo by DPP-4. These peptidyl hormones aresecreted by endocrine cells that are located in the epithelium of thesmall intestine. When these endocrine cells sense an increase in theconcentration of glucose in the lumen of the digestive tract, they actas the trigger for incretin release. Incretins are carried through thecirculation to beta cells in the pancreas and cause the beta cells tosecrete more insulin in anticipation of an increase of blood glucoseresulting from the digesting meal. Further studies indicating that theGPR40 modulatory role on the release of incretins from theenteroendocrine cells, including CCK, GLP-1, GIP, PYY, and possiblyothers, suggest that GPR40 modulators may contribute to enhanced insulinrelease from the pancreatic beta cells also indirectly by e.g. asynergistic effect of GLP-1 and possibly GIP on the insulin release, andthe other release incretins may also contribute to an overall beneficialcontribution of GPR40 modulation on metabolic diseases. The indirectcontributions of GPR40 modulation on insulin release through theelevation of plasma levels of incretins may be further augmented by thecoadministration of inhibitors of the enzymes responsible for theincretin degradation, such as inhibitors of DPP-4.

Insulin imbalances lead to conditions such as type II diabetes mellitus,a serious metabolic disease. The modulation of the function of GPR40 inmodulating insulin secretion indicates the therapeutic agents capable ofmodulating GPR40 function could be useful for the treatment of disorderssuch as diabetes and conditions associated with the disease, includinginsulin resistance, obesity, cardiovascular disease and dyslipidemia.

OBJECT OF THE PRESENT INVENTION

The object of the present invention is to provide new compounds,hereinafter described as compounds of formula I, in particular newindanyloxydihydrobenzofuranylacetic acids, which are active with regardto the G-protein-coupled receptor GPR40, notably are agonists of theG-protein-coupled receptor GPR40.

A further object of the present invention is to provide new compounds,in particular new indanyloxydihydrobenzofuranylacetic acids, which havean activating effect on the G-protein-coupled receptor GPR40 in vitroand/or in vivo and possess suitable pharmacological and pharmacokineticproperties to use them as medicaments.

A further object of the present invention is to provide effective GPR40agonists, in particular for the treatment of metabolic disorders, forexample diabetes, dyslipidemia and/or obesity.

A further object of the present invention is to provide methods fortreating a disease or condition mediated by the activation theG-protein-coupled receptor GPR40 in a patient.

A further object of the present invention is to provide a pharmaceuticalcomposition comprising at least one compound according to the invention.

A further object of the present invention is to provide a combination ofat least one compound according to the invention with one or moreadditional therapeutic agents.

Further objects of the present invention become apparent to the oneskilled in the art by the description hereinbefore and in the followingand by the examples.

GPR40 modulators are known in the art, for example, the compoundsdisclosed in WO 2004041266 (EP 1559422), WO 2007033002 and WO2009157418. The indanyloxydihydrobenzofuranylacetic acids of the presentinvention may provide several advantages, such as enhanced potency, highmetabolic and/or chemical stability, high selectivity and tolerability,enhanced solubility, and the possibility to form stable salts.

SUMMARY OF THE INVENTION

In a first aspect the invention relates to a compound of formula I

wherein

-   R¹ is selected from the group R¹-G1 consisting of phenyl-CH₂— and    heteroaryl-CH₂—,    -   wherein phenyl and heteroaryl are optionally substituted with 1        to 5 R³ groups, and both —CH₂— moieties are optionally        substituted with 1 or 2 H₃C— groups,    -   wherein heteroaryl is a 5-membered heteroaromatic ring which        contains 1 —NH-group, 1-O—, or —S— atom, or        -   a 5-membered heteroaromatic ring which contains 1 —NH—            group, 1-O— or —S-atom and additionally 1 or 2 ═N— atoms, or        -   a 6-membered heteroaromatic ring which contains 1, 2 or 3            ═N— atoms;-   R² is selected from the group R²-G1 consisting of F, Cl, Br, NC—,    F₂HC—, F₃C—, F₂HC—O—, and F₃C—O—;-   R³ is selected from the group R³-G1 consisting of F, Cl, Br, I, NC—,    C₂N—, H₂N—, C₁₋₄-alkyl-NH—, (C₁₋₄-alkyl)₂N—, C₁₋₄-alkyl,    C₂₋₄-alkenyl, C₂₋₄-alkinyl, HO—, HO—C₁₋₄-alkyl, C₁₋₄-alkyl-O—,    C₁₋₄-alkyl-O—C₁₋₄-alkyl, C₁₋₄-alkyl-S—, C₁₋₄-alkyl-S(═O)—,    C₁₋₄-alkyl-S(═O)₂—, C₃₋₆-cycloalkyl-, and C₃₋₆-cycloalkyl-O—,    wherein any alkyl and cycloalkyl group or submoiety is optionally    substituted with 1 to 5 fluorine atoms, preferably with 1 to 3    fluorine atoms; and    m is an integer selected from 1 and 2;    wherein in any definition mentioned hereinbefore and if not    specified otherwise, any alkyl group or sub-group may be    straight-chained or branched,    the isoforms, tautomers, stereoisomers, metabolites, prodrugs,    solvates, hydrates, and the salts thereof, particularly the    physiologically acceptable salts thereof with inorganic or organic    acids or bases, or the combinations thereof.

The extension -Gn used within the definitions is meant to identify genusn of the respective substituent. For example, R¹-G1 defines genus 1 ofthe substituent R¹.

In a further aspect this invention relates to a pharmaceuticalcomposition, comprising one or more compounds of general formula I orone or more pharmaceutically acceptable salts thereof according to theinvention, optionally together with one or more inert carriers and/ordiluents.

In a further aspect this invention relates to a method for treatingdiseases or conditions which are mediated by activating theG-protein-coupled receptor GPR40 in a patient in need thereofcharacterized in that a compound of general formula I or apharmaceutically acceptable salt thereof is administered to the patient.

According to another aspect of the invention, there is provided a methodfor treating a metabolic disease or disorder, such as diabetes,dyslipidemia and/or obesity, in a patient in need thereof characterizedin that a therapeutically effective amount of a compound of generalformula I or a pharmaceutically acceptable salt thereof is administeredto the patient.

According to another aspect of the invention, there is provided the useof a compound of the general formula I or a pharmaceutically acceptablesalt thereof for the manufacture of a medicament for a therapeuticmethod as described hereinbefore and hereinafter.

According to another aspect of the invention, there is provided acompound of the general formula I or a pharmaceutically acceptable saltthereof for use in a therapeutic method as described hereinbefore andhereinafter.

In a further aspect this invention relates to a method for treating adisease or condition mediated by the activation of the G-protein-coupledreceptor GPR40 in a patient that includes the step of administering tothe patient in need of such treatment a therapeutically effective amountof a compound of the general formula I or a pharmaceutically acceptablesalt thereof in combination with a therapeutically effective amount ofone or more additional therapeutic agents.

In a further aspect this invention relates to the use of a compound ofthe general formula I or a pharmaceutically acceptable salt thereof incombination with one or more additional therapeutic agents for thetreatment of diseases or conditions which are mediated by the activationof the G-protein-coupled receptor GPR40.

In a further aspect this invention relates to a pharmaceuticalcomposition which comprises a compound according to general formula I ora pharmaceutically acceptable salt thereof and one or more additionaltherapeutic agents, optionally together with one or more inert carriersand/or diluents.

Other aspects of the invention become apparent to the one skilled in theart from the specification and the experimental part as describedhereinbefore and hereinafter.

DETAILED DESCRIPTION

Unless otherwise stated, the groups, residues, and substituents,particularly R¹, R², R³, and m are defined as above and hereinafter. Ifresidues, substituents, or groups occur several times in a compound,they may have the same or different meanings. Some preferred meanings ofindividual groups and substituents of the compounds according to theinvention will be given hereinafter. Any and each of these definitionsmay be combined with each other.

R¹: R¹-G1:

The group R¹ is preferably selected from the group R¹-G1 as definedhereinbefore.

R¹-G2:

According to one embodiment the group R¹ is selected from the groupR¹-G2 consisting of phenyl-CH₂— and heteroaryl-CH₂,

-   wherein the phenyl ring is optionally substituted with 1 to 5 groups    independently selected from R³, the heteroaryl ring is optionally    substituted with 1 to 3 groups independently selected from R³, and    both —CH₂— moieties are optionally substituted with 1 or 2 H₃C—    groups, and-   wherein heteroaryl is a 5-membered heteroaromatic ring which    contains 1 —NH-group, 1 —O— or —S— atom and additionally 1 or 2 ═N—    atoms, or a 6-membered heteroaromatic ring which contains 1 or 2 ═N—    atoms.

R¹-G3:

According to one embodiment the group R¹ is selected from the groupR¹-G3 consisting of

-   wherein the phenyl group and each heteroaromatic group is optionally    substituted with 1 to 3 groups independently selected from R³, and    each —CH₂— moiety is optionally substituted with 1 or 2 H₃C— groups.

R¹-G4:

In another embodiment the group R¹ is selected from the group R¹-G4consisting of

-   wherein the phenyl and pyridyl group are optionally substituted with    1 to 3 groups independently selected from R³, and both —CH₂—    moieties are optionally substituted with 1 or 2 H₃C— groups.

R¹-G4a:

In another embodiment the group R¹ is selected from the group R¹-G4aconsisting of

-   wherein the phenyl group is optionally substituted with 1 to 3    groups independently selected from R³, and the —CH₂— moiety is    optionally substituted with 1 or 2 H₃C-groups.

R¹-G4b:

In another embodiment the group R¹ is selected from the group R¹-G4bconsisting of

-   wherein the phenyl group is optionally substituted with 1 to 3    groups independently selected from R³.

R¹-G5:

In another embodiment the group R¹ is selected from the group R¹-G5consisting of

R¹-G5a:

In another embodiment the group R¹ is selected from the group R¹-G5aconsisting of

R²: R²-G1:

The group R² is preferably selected from the group R²-G1 as definedhereinbefore.

R²-G2:

In another embodiment the group R² is selected from the group R²-G2consisting of F, Cl, F₃C—, NC—, and F₃C—O—.

R²-G3:

In another embodiment the group R² is selected from the group R²-G3consisting of F, F₃C—, and NC—.

R³: R³-G1:

The group R³ is preferably selected from the group R³-G1 as definedhereinbefore.

R³-G2:

In another embodiment the group R³ is selected from the group R³-G2consisting of F, Cl, Br, NC—, C₁₋₄-alkyl-NH—, (C₁₋₄-alkyl)₂N—,C₁₋₄-alkyl, F₂HC—, F₃C—, HO—, HO—C₁₋₄-alkyl, C₁₋₄-alkyl-O—, F₂HC—O—,F₃C—O—, C₁₋₄-alkyl-O—C₁₋₄-alkyl, C₁₋₄-alkyl-S—, C₁₋₄-alkyl-S(═O)—,C₁₋₄-alkyl-S(═O)₂—, C₃₋₆-cycloalkyl-, and C₃₋₆-cycloalkyl-O—.

R³-G3:

In another embodiment the group R³ is selected from the group R³-G3consisting of F, Cl, NC—, C₁₋₄-alkyl, F₂HC—, F₃C—, HO—, HO—C₁₋₄-alkyl,C₁₋₄-alkyl-O—, F₂HC—O—, F₃C—O—, C₁₋₄-alkyl-O—C₁₋₄-alkyl, C₁₋₄-alkyl-S—,C₁₋₄-alkyl-S(═O)—, C₁₋₄-alkyl-S(═O)₂—, C₃₋₆-cycloalkyl-, andC₄₋₆-cycloalkyl-O—.

R³-G4:

In another embodiment the group R³ is selected from the group R³-G4consisting of F, Cl, NC—, H₃C—, F₂HC—, F₃C—, HO—, HO—CH₂—, H₃C—O—,F₂HC—O—, F₃C—O—, H₃C—O—CH₂—, H₃C—S—, H₃C—S(═O)—, and H₃C—S(═O)₂—.

R³-G5:

In another embodiment the group R³ is selected from the group R³-G5consisting of C₁, H₃C—, NC—, HO—, H₃C—O—, H₃C—S—, H₃C—S(═O)—, andH₃C—S(═O)₂—.

R³-G5a:

In another embodiment the group R³ is selected from the group R³-G5consisting of F, Cl, H₃C—, NC—, HO—, H₃C—O—, H₃C—S—, H₃C—S(═O)—, andH₃C—S(═O)₂—.

m denotes 1 or 2, preferably 1.

The following preferred embodiments of compounds of the formula I aredescribed using generic formulae I.1 to I.3, wherein any tautomers,solvates, hydrates and salts thereof, in particular the pharmaceuticallyacceptable salts thereof, are encompassed.

Examples of preferred subgeneric embodiments (E) according to thepresent invention are set forth in the following table, wherein eachsubstituent group of each embodiment is defined according to thedefinitions set forth hereinbefore and wherein all other substituents ofthe formulas I and I.1 are defined according to the definitions setforth hereinbefore:

E R¹- R²- R³- m E-1 R¹-G1 R²-G1 R³-G1 1, 2 E-2 R¹-G1 R²-G1 R³-G2 1, 2E-3 R¹-G1 R²-G1 R³-G3 1, 2 E-4 R¹⁻G2 R²-G1 R³-G1 1, 2 E-5 R¹-G2 R²-G1R³-G2 1, 2 E-6 R¹-G2 R²-G1 R³-G3 1, 2 E-7 R¹-G3 R²-G1 R³-G1 1, 2 E-8R¹-G3 R²-G1 R³-G2 1, 2 E-9 R¹-G3 R²-G1 R³-G3 1, 2 E-10 R¹-G4a R²-G1R³-G1 1, 2 E-11 R¹-G4a R²-G1 R³-G2 1, 2 E-12 R¹-G4a R²-G1 R³-G3 1, 2E-13 R¹-G4a R²-G1 R³-G4 1, 2 E-14 R¹-G2 R²-G2 R³-G1 1, 2 E-15 R¹-G2R²-G2 R³-G2 1, 2 E-16 R¹-G2 R²-G2 R³-G3 1, 2 E-17 R¹-G2 R²-G2 R³-G4 1, 2E-18 R¹-G2 R²-G2 R³-G5 1, 2 E-19 R¹-G2 R²-G3 R³-G1 1, 2 E-20 R¹-G2 R²-G3R³-G2 1, 2 E-21 R¹-G2 R²-G3 R³-G3 1, 2 E-22 R¹-G2 R²-G3 R³-G4 1, 2 E-23R¹-G2 R²-G3 R³-G5 1, 2 E-24 R¹-G3 R²-G2 R³-G1 1, 2 E-25 R¹-G3 R²-G2R³-G2 1, 2 E-26 R¹-G3 R²-G2 R³-G3 1, 2 E-27 R¹-G3 R²-G2 R³-G4 1, 2 E-28R¹-G3 R²-G2 R³-G5 1, 2 E-29 R¹-G4a R²-G2 R³-G1 1, 2 E-30 R¹-G4a R²-G2R³-G2 1, 2 E-31 R¹-G4a R²-G2 R³-G3 1, 2 E-32 R¹-G4a R²-G2 R³-G4 1, 2E-33 R¹-G4a R²-G2 R³-G5 1, 2 E-34 R¹-G3 R²-G3 R³-G1 1, 2 E-35 R¹-G3R²-G3 R³-G2 1, 2 E-36 R¹-G3 R²-G3 R³-G3 1, 2 E-37 R¹-G3 R²-G3 R³-G4 1, 2E-38 R¹-G3 R²-G3 R³-G5 1, 2 E-39 R¹-G4a R²-G3 R³-G1 1, 2 E-40 R¹-G4aR²-G3 R³-G2 1, 2 E-41 R¹-G4a R²-G3 R³-G3 1, 2 E-42 R¹-G4a R²-G3 R³-G4 1,2 E-43 R¹-G4a R²-G3 R³-G5 1, 2 E-44 R¹-G4b R²-G3 R³-G1 1, 2 E-45 R¹-G4bR²-G3 R³-G2 1, 2 E-46 R¹-G4b R²-G3 R³-G3 1, 2 E-47 R¹-G4b R²-G3 R³-G4 1,2 E-48 R¹-G4b R²-G3 R³-G5 1, 2 E-49 R¹-G5 R²-G1 — 1, 2 E-50 R¹-G5 R²-G2— 1, 2 E-51 R¹-G5a R²-G3 — 1

Preferred are those compounds of formula I and I.1, wherein

R¹ is selected from the group consisting of

-   wherein the phenyl group and each heteroaromatic group is optionally    substituted with 1 to 3 groups independently selected from R³, and    each —CH₂— moiety is optionally substituted with 1 or 2 H₃C— groups;    R² is selected from the group consisting of F, Cl, F₃C—, NC—, and    F₃C—O—;    R³ is selected from the group consisting of F, Cl, NC—, C₁₋₄-alkyl,    F₂HC—, F₃C—, HO—, HO—C₁₋₄-alkyl, C₁₋₄-alkyl-O—, F₂HC—O—, F₃C—O—,    C₁₋₄-alkyl-O—C₁₋₄-alkyl, C₁₋₄-alkyl-S—, C₁₋₄-alkyl-S(═O)—,    C₁₋₄-alkyl-S(═O)₂—, C₃₋₆-cycloalkyl-, and C₄₋₆-cycloalkyl-O—; and    m is 1 or 2, preferably 1; and the pharmaceutically acceptable salts    thereof.

More preferred are those compounds of formula I and I.1, wherein

R¹ is

wherein the phenyl group is optionally substituted with 1 to 3 groupsindependently selected from R³, and the —CH₂— moiety is optionallysubstituted with 1 or 2 H₃C— groups;

R² is selected from the group consisting of F, F₃C—, and NC—;

R³ is selected from the group consisting of F, Cl, NC—, C₁₋₄-alkyl,F₂HC—, F₃C—, HO—, HO—C₁₋₄-alkyl, C₁₋₄-alkyl-O—, F₂HC—O—, F₃C—O—,C₁₋₄-alkyl-O—C₁₋₄-alkyl, C₁₋₄-alkyl-S—, C₁₋₄-alkyl-S(═O)—,C₁₋₄-alkyl-S(═O)₂—, C₃₋₆-cycloalkyl-, and C₄₋₆-cycloalkyl-O—; and

m is 1 or 2, preferably 1; and the pharmaceutically acceptable saltsthereof.

Particularly preferred are those compounds of formula I and I.1, wherein

R¹ is

wherein the phenyl group is optionally substituted with 1 to 3 groupsindependently selected from R³;R² is selected from the group consisting of F, F₃C—, and NC—;R³ is selected from the group consisting of F, Cl, NC—, C₁₋₄-alkyl,F₂HC—, F₃C—, HO—, HO—C₁₋₄-alkyl, C₁₋₄-alkyl-O—, F₂HC—O—, F₃C—O—,C₁₋₄-alkyl-O—C₁₋₄-alkyl, C₁₋₄-alkyl-S—, C₁₋₄-alkyl-S(═O)—,C₁₋₄-alkyl-S(═O)₂—, C₃₋₆-cycloalkyl-, and C₄₋₆-cycloalkyl-O—; andm is 1 or 2, preferably 1; and the pharmaceutically acceptable saltsthereof.

Particularly preferred compounds, including their tautomers andstereoisomers, the salts thereof, or any solvates or hydrates thereof,are described in the experimental section hereinafter.

The compounds according to the invention and their intermediates may beobtained using methods of synthesis which are known to the one skilledin the art and described in the literature of organic synthesis.Preferably the compounds are obtained analogously to the methods ofpreparation explained more fully hereinafter, in particular as describedin the experimental section. In some cases the sequence adopted incarrying out the reaction schemes may be varied. Variants of thesereactions that are known to the skilled man but are not described indetail here may also be used. The general processes for preparing thecompounds according to the invention will become apparent to the skilledman on studying the schemes that follow. Starting compounds arecommercially available or may be prepared by methods that are describedin the literature or herein, or may be prepared in an analogous orsimilar manner. Before the reaction is carried out any correspondingfunctional groups in the compounds may be protected using conventionalprotecting groups. These protecting groups may be cleaved again at asuitable stage within the reaction sequence using methods familiar tothe skilled man.

The compounds of the invention I are preferably accessed from aprecursor 1 that bears the carboxylic acid function in a protected ormasked form as sketched in Scheme 1; R¹, R², and m have the meanings asdefined hereinbefore and hereinafter. Suited precursor groups for thecarboxylic acid may be, e.g., a carboxylic ester, a carboxylic amide,cyano, an olefin, oxazole, or a thiazole. All these groups have beentransformed into the carboxylic acid function by different means whichare described in the organic chemistry literature and are known to theone skilled in the art. The preferred precursor group is a C₁₋₄-alkyl orbenzyl carboxylate, each of which may be additionally mono- orpolysubstituted with fluorine, methyl, and/or methoxy. These estergroups may be hydrolysed with an acid, such as hydrochloric acid orsulfuric acid, or more preferably an alkali metal hydroxide, such aslithium hydroxide, sodium hydroxide, or potassium hydroxide, to yieldthe carboxylic acid function; the hydrolysis is preferably conducted inaqueous solvents, such as water and tetrahydrofuran, 1,4-dioxane,alcohol, e.g. methanol, ethanol, and isopropanol, or dimethyl sulfoxide,at 0 to 120° C. A tert-butyl ester is preferably cleaved under acidicconditions, e.g. trifluoroacetic acid or hydrochloric acid, in a solventsuch as dichloromethane, 1,4-dioxane, isopropanol, or ethyl acetate. Abenzyl ester is advantageously cleaved using hydrogen in the presence ofa transition metal, preferably palladium on carbon. Benzyl estersbearing electron donating groups, such as methoxy groups, on thearomatic ring may also be removed under oxidative conditions; cericammonium nitrate (CAN) or 2,3-dichloro-5,6-dicyanoquinone (DDQ) are twocommonly used reagents for this approach.

Compound 1, in turn, may be obtained from indane 2, which bears aleaving group, and phenol 3, which is decorated with the carboxylic acidprecursor group (Scheme 2); R¹, R², and m in Scheme 2 have the meaningsas defined hereinbefore and hereinafter. The leaving group LG in 2 isreplaced with the O in 3 via a nucleophilic substitution; suited LG maybe Cl, Br, I, methylsulfonyloxy, phenylsulfonyloxy, p-tolylsulfonyloxy,and trifluoromethylsulfonyloxy. The reaction is usually carried out inthe presence of a base, such as triethylamine, ethyldiisopropylamine,1,8-diazabicyclo[5.4.0]undecene, carbonates, e.g. Li₂CO₃, Na₂CO₃, K₂CO₃,and Cs₂CO₃, hydroxides, e.g. LiOH, NaOH, and KOH, alcoholates, e.g.NaOMe, NaOEt, and KOtBu, hydrides, e.g. NaH and KH, amides, e.g. NaNH₂,KN(SiMe₃)₂, and LiN(iPr)₂, and oxides, e.g. CaO and Ag₂O. Additives,such as silver salts, e.g. AgNO₃, AgOSO₂CF₃, and Ag₂CO₃, crown ethers,e.g. 12-crown-4, 15-crown-5, and 18-crown-6, hexamethylphosphorustriamide (HMPT), and 1,3-dimethyl-3,4,5,6-dihydro-2-pyrimidinone (DMPU),may be beneficial or even essential for the reaction to proceed.Preferred solvents are dimethylsulfoxide, N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidinone, acetonitrile, acetone,1,4-dioxane, tetrahydrofuran, alcohol, e.g. ethanol or isopropanol,water, or mixtures thereof, while not all of the solvents can becombined with each additive and base mentioned above. Suited reactiontemperatures range from −20 to 140° C.

An alternative reaction to combine building blocks 2 and 3 is theMitsunobu reaction or variations thereof (Scheme 3); R¹, R², and m inScheme 3 have the meanings as defined hereinbefore and hereinafter. Thereaction is usually conducted with a phosphine and an azodicarboxylicester or amide in tetrahydrofuran, 1,4-dioxane, diethyl ether, toluene,benzene, dichloromethane, or mixtures thereof, at −30 to 100° C.Phosphines often used are triphenylphosphine and tributylphosphine whichare commonly combined with dimethyl azodicarboxylate, diethylazodicarboxylate, diisopropyl azodicarboxylate, di-(4-chlorobenzyl)azodicarboxylate, dibenzyl azodicarboxylate, di-tert-butylazodicarboxylate, azodicarboxylic acid bis-(dimethylamide),azodicarboxylic acid dipiperidide, or azodicarboxylic acid dimorpholide.

Intermediate 2′ is conveniently obtained from indanone 4 which, in turn,may be prepared from phenylpropionic acid derivative 5 (Scheme 4); R¹,R², and m in Scheme 4 have the meanings as defined hereinbefore andhereinafter. For the intramolecular acylation (Friedel-Craftsacylation), 5→4, a considerable number of approaches has been reported.The reaction may be performed starting with a carboxylic acid,carboxylic ester, carboxylic anhydride, carboxylic chloride or fluoride,or a nitrile using a Lewis acid as catalyst. The following Lewis acidsare some of the more often used ones: hydrobromic acid, hydroiodic acid,hydrochloric acid, sulfuric acid, phosphoric acid, P₄O₁₀,trifluoroacetic acid, methanesulfonic acid, toluenesulfonic acid,trifluoromethanesulfonic acid, ClSO₃H, Sc(OSO₂CF₃)₃, Tb(OSO₂CF₃)₃,SnCl₄, FeCl₃, AlBr₃, AlCl₃, SbCl₅, BCl₃, BF₃, ZnCl₂, montmorillonites,POCl₃, and PCl₅. The reaction may be conducted, e.g., indichloromethane, 1,2-dichloroethane, nitrobenzene, chlorobenzene, carbondisulfide, mixtures thereof, or without an additional solvent in anexcess of the Lewis acid, at 0 to 180° C. Carboxylic acids arepreferably reacted in polyphosphoric acid at 0 to 120° C., whilecarboxylic chlorides are preferably reacted with AlCl₃ indichloromethane or 1,2-dichloroethane at 0 to 80° C.

The subsequent reduction of the keto group in Scheme 4 is a standardtransformation in organic synthesis, which may be accomplished withlithium borohydride, sodium borohydride, lithium aluminum hydride, ordiisobutylaluminum hydride. While sodium borohydride is employed inaqueous or alcoholic solution at 0 to 60° C., the other reducing agentsmentioned are preferably used in inert solvents, such astetrahydrofuran, diethyl ether, dichloromethane, and toluene, at −80 to60° C. The reduction of the keto group may also be conducted in astereoselective fashion providing the alcohol in enantiomericallyenriched or pure form. Suited chiral reducing agents are boranescombined with an enantiomerically pure [1,3,2]oxazaborol(Corey-Bakshi-Shibata reaction or Corey-Itsuno reaction) or formic acid,formates, hydrogen, or silanes in the presence of an enantiomericallypure transition metal catalyst. Typical reaction conditions for theformer approach are borane (complexed with, e.g., dimethyl sulfide) and(R)- or(S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborolin, e.g., dichloromethane, toluene, methanol, tetrahydrofuran, ormixtures thereof, at 0 to 60° C. Using a chiral transition metalcatalyst, such as a ruthenium complex, e.g.chloro{[(1S,2S)-(−)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)-amido}-(mesitylene)ruthenium(II),may deliver the hydroxy compound with high enantiomeric excess using,e.g., formic acid in the presence of a base, e.g. triethylamine, indichloromethane, at −20 to 60° C.

Alternatively, indanone 4 can be synthesized as described in Scheme 5;R¹, R², and m have the meanings as defined hereinbefore and hereinafter.Starting with benzene 6 and 3-halo-propionic acid or a derivativethereof or acrylic acid or a derivative thereof the required indanone 4may be obtained via the combination of a Friedel-Crafts alkylation andacylation reaction in one pot or two separate reactions (eq. 1.)). Thesereactions are catalyzed by a Lewis acid, such as triflic acid, sulfuricacid, phosphoric acid, AlCl₃, ZnCl₂, and phosphorus pentoxide, andpreferably conducted without additional solvent in an excess of theLewis acid or in dichloromethane, 1,2-dichloroethane, cyclohexane, orcarbon disulfide, at 0 to 140° C. A preferred combination comprisescompound 6,3-chloro-propionyl chloride, and AlCl₃ in dichloromethane or1,2-dichlorethane at 20 to 80° C.

Starting with ethynylbenzene 7 indanone 4 is accessible by a transitionmetal catalyzed reaction with carbon monoxide (eq. 2.)). Rhodium is apreferred catalyst basis which is combined with a phosphine, e.g.triphenylphosphine, and a base, e.g. triethylamine, and used in asolvent, preferably tetrahydrofuran, at high carbon monoxide pressure,preferably 50 to 150 bar, at 150 to 200° C. (see e.g. J. Org. Chem.1993, 58, 5386-92).

Combination of 2-halo or pseudo-halo substituted styrene 8 and carbonmonoxide in the presence of a transition metal also allows thepreparation of indanone 4 (eq. 3.)). Palladium catalysts are preferredand used with carbon monoxide or molybdenum hexacarbonyl as carbonmonoxide source. Preferred solvents are N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidone, and 1,4-dioxane which arepreferably employed at 20 to 150° C. by conventional heating ormicrowave irradiation. Pyridine and tetrabutylammonium chloride arepreferred additives for this transformation (see e.g. J. Am. Chem. Soc.2003, 125, 4804-7 and J. Org. Chem. 2005, 70, 346-9).

Common synthetic routes to building block 3 are summarized in Scheme 6.2-Iodo or bromo ether 9 can be transformed into indane 3 via addition ofan in situ generated carbon anion or radical to the double bond andsubsequent trapping of the cyclic anion by a proton and the cyclicradical by a hydride source (eq. 1.)). nBuLi, iPrMgCl, iPrMgCl*LiCl, Mg,Mg*LiCl, Zn, and Zn*LiCl are preferred reagents to convert the C—I orC—Br bond into a C-M bond (M=Li, Mgl, Znl etc.) with sufficientnucleophilicity to add to the double bond. The reactions with lithiumand magnesium reagents are preferably conducted in hexanes,tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, toluene, ormixtures thereof, at −100 to 60° C. Zn is preferably used intetrahydrofuran, dimethyl sulfoxide, N-methylpyrrolidinone, or mixturesthereof, at 0 to 100° C. Frequently employed reaction conditions for theradical pathway are, e.g., tributyltin hydride, azobisisobutyronitrile,in benzene, at 60 to 100° C. (see e.g. J. Org. Chem. 1987, 52, 4072-8);and NaH₃B(CN) in N,N-dimethylformamide under UV irradiation at 20 to120° C. (see e.g. Synlett 2005, 2248-50).

Combination of allyl ether 10 with carbon monoxide is anotherpossibility to obtain indane 3 (equation 2.)). The reaction ispreferably conducted with a palladium catalyst in the presence of carbonmonoxide or molybdenum hexacarbonyl as carbon monoxide source (see e.g.Tetrahedron Lett. 2010, 51, 2102-5).

Starting from benzofuran 11 or dihydrobenzofuran 12 indane 3 is yieldedafter reduction of the double bond. Hydrogen is the preferred reducingagent which is mainly employed in combination with a transition metalcatalyst, such as palladium on carbon, Raney nickel, and PtO₂.N,N-dimethylformamide, tetrahydrofuran, ethyl acetate, alcohol, e.g.methanol and ethanol, acetic acid, water, or mixtures thereof arepreferably used as solvent, at hydrogen pressures of 1 to 100 bar, andtemperatures of 20 to 120° C. This reaction may also be carried outstereoselectively providing compound 3 in enantiomerically enriched orpure form.

The syntheses of the starting compounds in Scheme 6 comprise standardprocedures used in organic synthesis. Intermediate 11 can, for example,be prepared as described in Scheme 7. Compound 11 may thus be obtainedfrom compound 13 which, in turn, may be assembled from phenol 14 andester 15. The latter transformation may be achieved in the presence of aLewis acid, e.g. sulfuric acid, ZrCl₄, InCl₃, methanesulfonic acid,p-toluenesulfonic acid, HI, or amberlyst, in toluene, dichloromethane,acetic acid, ethanol, water, or without a solvent in an excess of theLewis acid, at 0 to 120° C. Transformation of compound 13 intointermediate 11 is preferably accomplished under basic conditions withsodium hydroxide in an aqueous solution at 0 to 100° C.

Residue R¹ may be attached to the benzo part of the compounds of theinvention via a transition metal catalyzed reaction at almost any stageof the reaction sequence (Scheme 8); R¹, R², and m have the meanings asdefined hereinbefore and hereinafter. R¹ is preferably used asnucleophilic reaction partner bearing a metal residue at the benzyliccarbon atom; suited metal residues may be magnesium halides or pseudohalides, zinc halides or pseudo halides, boronic acid, boronic esters,and trifluoroborates. The benzo part is preferably employed aselectrophilic reaction partner bearing a leaving group such as Cl, Br,I, triflate, mesylate, or tosylate. Suitable transition metal catalystsare derived from palladium, nickel, copper, or iron. The active catalystmay be an elemental form of the transition metal, such as palladium oncarbon or nanoparticles of iron or palladium, or a salt of thetransition metal, such as fluoride, chloride, bromide, acetate,triflate, or trifluoroacetate, which are preferably combined withligands, such as phosphines, e.g. tri-tert-butylphosphine,tricyclohexylphosphine, optionally substitutedbiphenyl-dicyclohexyl-phosphines, optionally substitutedbiphenyl-di-tert-butyl-phosphines,1,1′-bis(diphenylphosphino)-ferrocene, triphenylphosphine,tritolylphosphine, or trifurylphosphine, phosphites, 1,3-disubstitutedimidazole carbenes, 1,3-disubstituted imidazolidine carbenes,dibenzylideneacetone, allyl, or nitriles. Depending on the reactvity ofthe nucleophile, the reaction may be conducted in benzene, toluene,ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone,alcohol, water, or mixtures thereof, at −10 to 160° C. Additives such ashalide salts, e.g. lithium chloride, potassium fluoride,tetrabutylammonium fluoride, hydroxide sources, such as potassiumhydroxide, sodium or potassium carbonate, amines, such as triethylamine,diisopropylamine, and ethyldiisopropylamine, silver salts, such assilver triflate, and/or copper salts, such as copper iodide or chloride,may be beneficial or even essential for the reaction to proceed.

The reactivities of the reaction partners (reacting carbons) describedmay be reversed, i.e. compound 16 is the nucleophile bearing M andcompound 17 is the electrophile bearing the leaving group, providing thesame product under the same or similar conditions.

The synthetic routes presented may rely on the use of protecting groups.For example, potentially reactive groups present, such as hydroxy,carbonyl, carboxy, amino, alkylamino, or imino, may be protected duringthe reaction by conventional protecting groups which are cleaved againafter the reaction. Suitable protecting groups for the respectivefunctionalities and their removal are well known to the one skilled inthe art and are described in the literature of organic synthesis.

The compounds of general formula I may be resolved into theirenantiomers and/or diastereomers as mentioned below. Thus, for example,cis/trans mixtures may be resolved into their cis and trans isomers andracemic compounds may be separated into their enantiomers.

The cis/trans mixtures may be resolved, for example, by chromatographyinto the cis and trans isomers thereof. The compounds of general formulaI which occur as racemates may be separated by methods known per se intotheir optical antipodes and diastereomeric mixtures of compounds ofgeneral formula I may be resolved into their diastereomers by takingadvantage of their different physico-chemical properties using methodsknown per se, e.g. chromatography and/or fractional crystallization; ifthe compounds obtained thereafter are racemates, they may be resolvedinto the enantiomers as mentioned below.

The racemates are preferably resolved by column chromatography on chiralphases or by crystallization from an optically active solvent or byreacting with an optically active substance which forms salts orderivatives such as esters or amides with the racemic compound. Saltsmay be formed with enantiomerically pure acids for basic compounds andwith enantiomerically pure bases for acidic compounds. Diastereomericderivatives are formed with enantiomerically pure auxiliary compounds,e.g. acids, their activated derivatives, or alcohols. Separation of thediastereomeric mixture of salts or derivatives thus obtained may beachieved by taking advantage of their different physico-chemicalproperties, e.g. differences in solubility; the free antipodes may bereleased from the pure diastereomeric salts or derivatives by the actionof suitable agents. Optically active acids commonly used for such apurpose as well as optically active alcohols applicable as auxiliaryresidues are known to those skilled in the art.

As mentioned above, the compounds of formula I may be converted intosalts, particularly for pharmaceutical use into the pharmaceuticallyacceptable salts. As used herein, “pharmaceutically acceptable salts”refer to derivatives of the disclosed compounds wherein the parentcompound is modified by making acid or base salts thereof.

The compounds according to the invention are advantageously alsoobtainable using the methods described in the examples that follow,which may also be combined for this purpose with methods known to theskilled man from the literature.

TERMS AND DEFINITIONS

Terms not specifically defined herein should be given the meanings thatwould be given to them by one of skill in the art in light of thedisclosure and the context. As used in the specification, however,unless specified to the contrary, the following terms have the meaningindicated and the following conventions are adhered to.

The terms “compound(s) according to this invention”, “compound(s) offormula (I)”, “compound(s) of the invention” and the like denote thecompounds of the formula (I) according to the present inventionincluding their tautomers, stereoisomers and mixtures thereof and thesalts thereof, in particular the pharmaceutically acceptable saltsthereof, and the solvates and hydrates of such compounds, including thesolvates and hydrates of such tautomers, stereoisomers and saltsthereof.

The terms “treatment” and “treating” embrace both preventative, i.e.prophylactic, or therapeutic, i.e. curative and/or palliative,treatment. Thus the terms “treatment” and “treating” comprisetherapeutic treatment of patients having already developed saidcondition, in particular in manifest form. Therapeutic treatment may besymptomatic treatment in order to relieve the symptoms of the specificindication or causal treatment in order to reverse or partially reversethe conditions of the indication or to stop or slow down progression ofthe disease. Thus the compositions and methods of the present inventionmay be used for instance as therapeutic treatment over a period of timeas well as for chronic therapy. In addition the terms “treatment” and“treating” comprise prophylactic treatment, i.e. a treatment of patientsat risk to develop a condition mentioned hereinbefore, thus reducingsaid risk.

When this invention refers to patients requiring treatment, it relatesprimarily to treatment in mammals, in particular humans.

The term “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats or prevents theparticular disease or condition, (ii) attenuates, ameliorates, oreliminates one or more symptoms of the particular disease or condition,or (iii) prevents or delays the onset of one or more symptoms of theparticular disease or condition described herein.

The terms “modulated” or “modulating”, or “modulate(s)”, as used herein,unless otherwise indicated, refer to the activation of theG-protein-coupled receptor GPR40 with one or more compounds of thepresent invention.

The terms “mediated” or “mediating” or “mediate”, as used herein, unlessotherwise indicated, refer to the (i) treatment, including prevention ofthe particular disease or condition, (ii) attenuation, amelioration, orelimination of one or more symptoms of the particular disease orcondition, or (iii) prevention or delay of the onset of one or moresymptoms of the particular disease or condition described herein.

The term “substituted” as used herein, means that any one or morehydrogens on the designated atom, radical or moiety is replaced with aselection from the indicated group, provided that the atom's normalvalence is not exceeded, and that the substitution results in anacceptably stable compound.

In the groups, radicals, or moieties defined below, the number of carbonatoms is often specified preceding the group, for example, C₁₋₆-alkylmeans an alkyl group or radical having 1 to 6 carbon atoms. In general,for groups comprising two or more subgroups, the last named subgroup isthe radical attachment point, for example, the substituent“aryl-C₁₋₃-alkyl-” means an aryl group which is bound to aC₁₋₃-alkyl-group, the latter of which is bound to the core or to thegroup to which the substituent is attached.

In case a compound of the present invention is depicted in form of achemical name and as a formula in case of any discrepancy the formulashall prevail.

An asterisk may be used in sub-formulas to indicate the bond which isconnected to the core molecule as defined.

The numeration of the atoms of a substituent starts with the atom whichis closest to the core or to the group to which the substituent isattached.

For example, the term “3-carboxypropyl-group” represents the followingsubstituent:

wherein the carboxy group is attached to the third carbon atom of thepropyl group. The terms “1-methylpropyl-”, “2,2-dimethylpropyl-” or“cyclopropylmethyl-” group represent the following groups:

The asterisk may be used in sub-formulas to indicate the bond which isconnected to the core molecule as defined.

In a definition of a group the term “wherein each X, Y and Z group isoptionally substituted with” and the like denotes that each group X,each group Y and each group Z either each as a separate group or each aspart of a composed group may be substituted as defined. For example adefinition “R^(ex) denotes H, C₁₋₃-alkyl, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyl-C₁₋₃-alkyl or C₁₋₃-alkyl-O—, wherein each alkyl group isoptionally substituted with one or more L^(ex).” or the like means thatin each of the beforementioned groups which comprise the term alkyl,i.e. in each of the groups C₁₋₃-alkyl, C₃₋₆-cycloalkyl-C₁₋₃-alkyl andC₁₋₃-alkyl-O—, the alkyl moiety may be substituted with L^(ex) asdefined.

Unless specifically indicated, throughout the specification and theappended claims, a given chemical formula or name shall encompasstautomers and all stereo, optical and geometrical isomers (e.g.enantiomers, diastereomers, E/Z isomers etc. . . . ) and racematesthereof as well as mixtures in different proportions of the separateenantiomers, mixtures of diastereomers, or mixtures of any of theforegoing forms where such isomers and enantiomers exist, as well assalts, including pharmaceutically acceptable salts thereof and solvatesthereof such as for instance hydrates including solvates of the freecompounds or solvates of a salt of the compound.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication, andcommensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof.

Salts of other acids than those mentioned above which for example areuseful for purifying or isolating the compounds of the present invention(e.g. trifluoro acetate salts) also comprise a part of the invention.

The term halogen generally denotes fluorine, chlorine, bromine andiodine.

The term “C_(1-n)-alkyl”, wherein n is an integer from 1 to n, eitheralone or in combination with another radical denotes an acyclic,saturated, branched or linear hydrocarbon radical with 1 to n C atoms.For example the term C₁₋₅-alkyl embraces the radicals H₃C—, H₃C—CH₂—,H₃C—CH₂—CH₂—, H₃C—CH(CH₃)—, H₃C—CH₂—CH₂—CH₂—, H₃C—CH₂—CH(CH₃)—,H₃C—CH(CH₃)—CH₂—, H₃C—C(CH₃)₂—, H₃C—CH₂—CH₂—CH₂—CH₂—,H₃C—CH₂—CH₂—CH(CH₃)—, H₃C—CH₂—CH(CH₃)—CH₂—, H₃C—CH(CH₃)—CH₂—CH₂—,H₃C—CH₂—C(CH₃)₂—, H₃C—C(CH₃)₂—CH₂—, H₃C—CH(CH₃)—CH(CH₃)— andH₃C—CH₂—CH(CH₂CH₃)—.

The term “C_(1-n)-alkylene” wherein n is an integer 1 to n, either aloneor in combination with another radical, denotes an acyclic, straight orbranched chain divalent alkyl radical containing from 1 to n carbonatoms. For example the term C₁₋₄-alkylene includes —(CH₂)—, —(CH₂—CH₂)—,—(CH(CH₃))—, —(CH₂—CH₂—CH₂)—, —(C(CH₃)₂)—, —(CH(CH₂CH₃))—,—(CH(CH₃)—CH₂)—, —(CH₂—CH(CH₃))—, —(CH₂—CH₂—CH₂—CH₂)—,—(CH₂—CH₂—CH(CH₃))—, —(CH(CH₃)—CH₂—CH₂)—, —(CH₂—CH(CH₃)—CH₂)—,—(CH₂—C(CH₃)₂)—, —(C (CH₃)₂—CH₂)—, —(CH(CH₃)—CH(CH₃))—,—(CH₂—CH(CH₂CH₃))—, —(CH(CH₂CH₃)—CH₂)—, —(CH(CH₂CH₂CH₃))—,—(CHCH(CH₃)₂)— and —C(CH₃)(CH₂CH₃)—.

The term “C_(2-n)-alkenyl”, is used for a group as defined in thedefinition for “C_(1-n)-alkyl” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a double bond. For example the term C₂₋₃-alkenyl includes —CH═CH₂,—CH═CH—CH₃, —CH₂—CH═CH₂.

The term “C_(2-n)-alkenylene” is used for a group as defined in thedefinition for “C_(1-n)-alkylene” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a double bond. For example the term C₂₋₃-alkenylene includes —CH═CH—,—CH═CH—CH₂—, —CH₂—CH═CH—.

The term “C_(2-n)-alkynyl”, is used for a group as defined in thedefinition for “C_(1-n)-alkyl” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a triple bond. For example the term C₂₋₃-alkynyl includes —C≡CH,—C≡C—CH₃, —CH₂—C≡CH.

The term “C_(2-n)-alkynylene” is used for a group as defined in thedefinition for “C_(1-n)-alkylene” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a triple bond. For example the term C₂₋₃-alkynylene includes —C≡C—,—C≡C—CH₂—, —CH₂—C≡C—.

The term “C_(3-n)-carbocyclyl” as used either alone or in combinationwith another radical, denotes a monocyclic, bicyclic or tricyclic,saturated or unsaturated hydrocarbon radical with 3 to n C atoms. Thehydrocarbon radical is preferably nonaromatic. Preferably the 3 to n Catoms form one or two rings. In case of a bicyclic or tricyclic ringsystem the rings may be attached to each other via a single bond or maybe fused or may form a spirocyclic or bridged ring system. For examplethe term C₃₋₁₀-carbocyclyl includes C₃₋₁₀-cylcoalkyl,C₃₋₁₀-cycloalkenyl, octahydropentalenyl, octahydroindenyl,decahydronaphthyl, indanyl, tetrahydronaphthyl. Most preferably the termC_(3-n)-carbocyclyl denotes C_(3-n)-cylcoalkyl, in particularC₃₋₇-cycloalkyl.

The term “C_(3-n)-cycloalkyl”, wherein n is an integer 4 to n, eitheralone or in combination with another radical denotes a cyclic,saturated, unbranched hydrocarbon radical with 3 to n C atoms. Thecyclic group may be mono-, bi-, tri- or spirocyclic, most preferablymonocyclic. Examples of such cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclononyl, cyclododecyl, bicyclo[3.2.1]octyl, spiro[4.5]decyl,norpinyl, norbonyl, norcaryl, adamantyl, etc.

The term “C_(3-n)-cycloalkenyl”, wherein n is an integer 3 to n, eitheralone or in combination with another radical, denotes a cyclic,unsaturated but nonaromatic, unbranched hydrocarbon radical with 3 to nC atoms, at least two of which are bonded to each other by a doublebond. For example the term C₃₋₇-cycloalkenyl includes cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl,cyclohexadienyl, cycloheptenyl, cycloheptadienyl and cycloheptatrienyl.

The term “aryl” as used herein, either alone or in combination withanother radical, unless specified otherwise, denotes a carbocyclicaromatic monocyclic group containing 6 carbon atoms which may be furtherfused to a second 5- or 6-membered carbocyclic group which may bearomatic, saturated or unsaturated. Aryl includes, but is not limitedto, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl,tetrahydronaphthyl and dihydronaphthyl. More preferably the term “aryl”as used herein, either alone or in combination with another radical,denotes phenyl or naphthyl, most preferably phenyl.

The term “heterocyclyl”, unless specified otherwise, means a saturatedor unsaturated mono-, bi-, tri- or spirocarbocyclic, preferably mono-,bi- or spirocyclic-ring system containing one or more heteroatomsselected from N, O or S(O)_(r) with r=0, 1 or 2, which in addition mayhave a carbonyl group. More preferably the term “heterocyclyl” as usedherein, either alone or in combination with another radical, means asaturated or unsaturated, even more preferably a saturated mono-, bi- orspirocyclic-ring system containing 1, 2, 3 or 4 heteroatoms selectedfrom N, O or S(O)_(r) with r=0, 1 or 2 which in addition may have acarbonyl group. The term “heterocyclyl” is intended to include all thepossible isomeric forms. Examples of such groups include aziridinyl,oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl,piperidinyl, tetrahydropyranyl, azepanyl, piperazinyl, morpholinyl,tetrahydrofuranonyl, tetrahydropyranonyl, pyrrolidinonyl, piperidinonyl,piperazinonyl, morpholinonyl.

Thus, the term “heterocyclyl” includes the following exemplarystructures which are not depicted as radicals as each form may beattached through a covalent bond to any atom so long as appropriatevalences are maintained:

The term “heteroaryl”, unless specified otherwise, means a mono- orpolycyclic, preferably mono- or bicyclic-ring system containing one ormore heteroatoms selected from N, O or S(O)_(r) with r=0, 1 or 2 whereinat least one of the heteroatoms is part of an aromatic ring, and whereinsaid ring system may have a carbonyl group. More preferably the term“heteroaryl” as used herein, either alone or in combination with anotherradical, means a mono- or bicyclic-ring system containing 1, 2, 3 or 4heteroatoms selected from N, O or S(O)_(r) with r=0, 1 or 2 wherein atleast one of the heteroatoms is part of an aromatic ring, and whereinsaid ring system may have a carbonyl group. The term “heteroaryl” isintended to include all the possible isomeric forms.

Thus, the term “heteroaryl” includes the following exemplary structureswhich are not depicted as radicals as each form may be attached througha covalent bond to any atom so long as appropriate valences aremaintained:

Many of the terms given above may be used repeatedly in the definitionof a formula or group and in each case have one of the meanings givenabove, independently of one another.

Pharmacological Activity

The activity of the compounds of the invention may be demonstrated usingthe following assays:

Assay I:

IP₁ accumulation measurements using the IPOne assay system—1321N1 cellsstably expressing human GPR40 receptor (Euroscreen, Belgium) are seeded24 h before the assay in black clear-bottom collagen-coated 384-wellplates in culture medium containing 10% FCS, 1% Na-Pyruvate and 400μg/mL G418. IP₁ is assayed according to the Manufacturer's description(Cisbio Bioassays, France). In brief, the assay is started bysubstitution of the culture medium by stimulation buffer (Hepes 10 mM,CaCl₂ 1 mM, MgCl₂ 0.5 mM, KCl 4.2 mM, NaCl 146 mM and glucose 5.5 mM, pH7.4) without LiCl. Cells are stimulated for 1 hour at 37° C., 10% CO₂ byaddition of the compounds that are diluted in stimulation buffercontaining LiCl yielding a final LiCl concentration of 50 mM. Assays arestopped by adding HTRF-conjugates (IP1-d2 and Anti-IP1 cryptate Tb) andlysis buffer, provided by the manufacturer. After an incubation time of1 hour at room temperature plates are measured using an EnVision™,Perkin Elmer. The obtained fluorescence ratios at 665/615 nM are thenused to calculate the pEC₅₀ values using GraphPad Prism 5 (GraphpadSoftware Inc, USA) by interpolation using an IP₁ reference curve andsubsequent sigmoidal curve fitting allowing for a variable hill slope.

The compounds according to the invention typically have EC₅₀ values inthe range from about 1 nM to about 10 μM, preferably less than 1 μM,more preferably less than 100 nM.

EC₅₀ values for compounds according to the invention determined in AssayI are shown in the following Table. The number of the compoundcorresponds to the number of the Example in the experimental section.

EC₅₀ EC₅₀ EC₅₀ EC₅₀ Example [nM] Example [nM] Example [nM] Example [nM]1 5 2 36 3 24 4 5 5 6 6 8 7 18 8 325 9 29 10 3 11 12 12 479 13 5 14 4 1535 16 5

Assay II:

IP₁ accumulation measurements using the IPOne assay system—1321N1 cellsstably expressing human GPR40 receptor (Euroscreen, Belgium) are seeded24 h before the assay in white 384-well plates in culture mediumcontaining 10% FCS, 1% Na-Pyruvate and 400 μg/mL G418. IP₁ is assayedaccording to the manufacturer's description (Cisbio Bioassays, France).In brief, the assay is started by substitution of the culture medium bystimulation buffer (Hepes 10 mM, CaCl₂ 1 mM, MgCl₂ 0.5 mM, KCl 4.2 mM,NaCl 146 mM, glucose 5.5 mM and LiCl 50 mM, pH 7.4). Cells arestimulated for 1 h at 37° C., 5% CO₂ by addition of the compounds thatare diluted in stimulation buffer containing LiCl. Assays are stopped byadding HTRF-conjugates (IP1-d2 and Anti-IP1 cryptate Tb) and lysisbuffer, provided by the manufacturer. After an incubation time of 1 h atroom temperature plates are measured using an EnVision™, Perkin Elmer.The obtained fluorescence ratios at 665/615 nM are then used tocalculate the pEC₅₀ values using Assay Explorer 3.3 Software (Accelrys,Inc.) by interpolation using an IP₁ reference curve and subsequentsigmoidal curve fitting allowing for a variable hill slope.

The compounds according to the invention typically have EC₅₀ values inthe range from about 1 nM to about 10 μM, preferably less than 1 μM,more preferably less than 100 nM.

EC₅₀ values for compounds according to the invention determined in AssayII are shown in the following table. The number of the compoundcorresponds to the number of the Example in the experimental section.

EC₅₀ EC₅₀ EC₅₀ EC₅₀ Example [nM] Example [nM] Example [nM] Example [nM]17 24 18 27 19 23 20 589 21 15 22 6 23 11 24 12 25 2 26 2 27 5 28 5 29 330 2 31 2 32 8 33 2 34 4 35 2 36 2 37 4 38 1 40 5

In view of their ability to modulate the activity of theG-protein-coupled receptor GPR40, in particular an agonistic activity,the compounds of general formula I according to the invention, includingthe corresponding salts thereof, are theoretically suitable for thetreatment of all those diseases or conditions which may be affected orwhich are mediated by the activation of the G-protein-coupled receptorGPR40.

Accordingly, the present invention relates to a compound of generalformula I as a medicament.

Furthermore, the present invention relates to the use of a compound ofgeneral formula I or a pharmaceutical composition according to thisinvention for the treatment and/or prevention of diseases or conditionswhich are mediated by the activation of the G-protein-coupled receptorGPR40 in a patient, preferably in a human.

In yet another aspect the present invention relates to a method fortreating a disease or condition mediated by the activation of theG-protein-coupled receptor GPR40 in a mammal that includes the step ofadministering to a patient, preferably a human, in need of suchtreatment a therapeutically effective amount of a compound or apharmaceutical composition of the present invention.

Diseases and conditions mediated by agonists of the G-protein-coupledreceptor GPR40 embrace metabolic diseases or conditions. According toone aspect the compounds and pharmaceutical compositions of the presentinvention are particularly suitable for treating diabetes mellitus, inparticular Type 2 diabetes, Type 1 diabetes, complications of diabetes(such as e.g. retinopathy, nephropathy or neuropathies, diabetic foot,ulcers or macroangiopathies), metabolic acidosis or ketosis, reactivehypoglycaemia, hyperinsulinaemia, glucose metabolic disorder, insulinresistance, metabolic syndrome, dyslipidaemias of different origins,atherosclerosis and related diseases, obesity, high blood pressure,chronic heart failure, oedema and hyperuricaemia.

The compounds and pharmaceutical compositions of the present inventionare also suitable for preventing beta-cell degeneration such as e.g.apoptosis or necrosis of pancreatic beta cells. The compounds andpharmaceutical compositions of the present invention are also suitablefor improving or restoring the functionality of pancreatic cells, andalso for increasing the number and size of pancreatic beta cells.

Therefore according to another aspect the invention relates to compoundsof formula I and pharmaceutical compositions according to the inventionfor use in preventing, delaying, slowing the progression of and/ortreating metabolic diseases, particularly in improving the glycaemiccontrol and/or beta cell function in the patient.

In another aspect the invention relates to compounds of formula I andpharmaceutical compositions according to the invention for use inpreventing, delaying, slowing the progression of and/or treating type 2diabetes, overweight, obesity, complications of diabetes and associatedpathological conditions.

In addition the compounds and pharmaceutical compositions according tothe invention are suitable for use in one or more of the followingtherapeutic processes:

-   -   for preventing, delaying, slowing the progression of or treating        metabolic diseases, such as for example type 1 diabetes, type 2        diabetes, insufficient glucose tolerance, insulin resistance,        hyperglycaemia, hyperlipidaemia, hypercholesterolaemia,        dyslipidaemia, syndrome X, metabolic syndrome, obesity, high        blood pressure, chronic systemic inflammation, retinopathy,        neuropathy, nephropathy, atherosclerosis, endothelial        dysfunction or bone-related diseases (such as osteoporosis,        rheumatoid arthritis or osteoarthritis);    -   for improving glycaemic control and/or reducing fasting plasma        glucose, postprandial plasma glucose and/or the glycosylated        haemoglobin HbA1c;    -   for preventing, delaying, slowing or reversing the progression        of disrupted glucose tolerance, insulin resistance and/or        metabolic syndrome to type 2 diabetes;    -   for preventing, delaying, slowing the progression of or treating        a condition or a disease selected from among the complications        of diabetes, such as for example retinopathy, nephropathy or        neuropathies, diabetic foot, ulcers or macroangiopathies;    -   for reducing weight or preventing weight gain or assisting        weight loss;    -   for preventing or treating the degradation of pancreatic beta        cells and/or improving and/or restoring the functionality of        pancreatic beta cells and/or restoring the functionality of        pancreatic insulin secretion;    -   for maintaining and/or improving insulin sensitivity and/or        preventing or treating hyperinsulinaemia and/or insulin        resistance.

In particular, the compounds and pharmaceutical compositions accordingto the invention are suitable for the treatment of obesity, diabetes(comprising type 1 and type 2 diabetes, preferably type 2 diabetesmellitus) and/or complications of diabetes (such as for exampleretinopathy, nephropathy or neuropathies, diabetic foot, ulcers ormacroangiopathies).

The compounds according to the invention are most particularly suitablefor treating type 2 diabetes mellitus.

The dose range of the compounds of general formula I applicable per dayis usually from 0.001 to 10 mg per kg body weight, for example from 0.01to 8 mg per kg body weight of the patient. Each dosage unit mayconveniently contain from 0.1 to 1000 mg, for example 0.5 to 500 mg.

The actual therapeutically effective amount or therapeutic dosage willof course depend on factors known by those skilled in the art such asage and weight of the patient, route of administration and severity ofdisease. In any case the compound or composition will be administered atdosages and in a manner which allows a therapeutically effective amountto be delivered based upon patient's unique condition.

The compounds, compositions, including any combinations with one or moreadditional therapeutic agents, according to the invention may beadministered by oral, transdermal, inhalative, parenteral or sublingualroute. Of the possible methods of administration, oral or intravenousadministration is preferred.

Pharmaceutical Compositions

Suitable preparations for administering the compounds of formula I,optionally in combination with one or more further therapeutic agents,will be apparent to those with ordinary skill in the art and include forexample tablets, pills, capsules, suppositories, lozenges, troches,solutions, syrups, elixirs, sachets, injectables, inhalatives andpowders etc. Oral formulations, particularly solid forms such as e.g.tablets or capsules are preferred. The content of the pharmaceuticallyactive compound(s) is advantageously in the range from 0.1 to 90 wt.-%,for example from 1 to 70 wt.-% of the composition as a whole.

Suitable tablets may be obtained, for example, by mixing one or morecompounds according to formula I with known excipients, for exampleinert diluents, carriers, disintegrants, adjuvants, surfactants, bindersand/or lubricants. The tablets may also consist of several layers. Theparticular excipients, carriers and/or diluents that are suitable forthe desired preparations will be familiar to the skilled man on thebasis of his specialist knowledge. The preferred ones are those that aresuitable for the particular formulation and method of administrationthat are desired. The preparations or formulations according to theinvention may be prepared using methods known per se that are familiarto the skilled man, such as for example by mixing or combining at leastone compound of formula I according to the invention, or apharmaceutically acceptable salt of such a compound, and one or moreexcipients, carriers and/or diluents.

Combination Therapy

The compounds of the invention may further be combined with one or more,preferably one additional therapeutic agent. According to one embodimentthe additional therapeutic agent is selected from the group oftherapeutic agents useful in the treatment of diseases or conditionsdescribed hereinbefore, in particular associated with metabolic diseasesor conditions such as for example diabetes mellitus, obesity, diabeticcomplications, hypertension, hyperlipidemia. Additional therapeuticagents which are suitable for such combinations include in particularthose which for example potentiate the therapeutic effect of one or moreactive substances with respect to one of the indications mentionedand/or which allow the dosage of one or more active substances to bereduced.

Therefore a compound of the invention may be combined with one or moreadditional therapeutic agents selected from the group consisting ofantidiabetic agents, agents for the treatment of overweight and/orobesity and agents for the treatment of high blood pressure, heartfailure and/or atherosclerosis.

Antidiabetic agents are for example metformin, sulphonylureas,nateglinide, repaglinide, thiazolidinediones, PPAR-(alpha, gamma oralpha/gamma) agonists or modulators, alpha-glucosidase inhibitors, DPPIVinhibitors, SGLT2-inhibitors, insulin and insulin analogues, GLP-1 andGLP-1 analogues or amylin and amylin analogues, cycloset, 11β-HSDinhibitors. Other suitable combination partners are inhibitors ofprotein tyrosinephosphatase 1, substances that affect deregulatedglucose production in the liver, such as e.g. inhibitors ofglucose-6-phosphatase, or fructose-1,6-bisphosphatase, glycogenphosphorylase, glucagon receptor antagonists and inhibitors ofphosphoenol pyruvate carboxykinase, glycogen synthase kinase or pyruvatedehydrokinase, alpha2-antagonists, CCR-2 antagonists or glucokinaseactivators. One or more lipid lowering agents are also suitable ascombination partners, such as for example HMG-CoA-reductase inhibitors,fibrates, nicotinic acid and the derivatives thereof, PPAR-(alpha, gammaor alpha/gamma) agonists or modulators, PPAR-delta agonists, ACATinhibitors or cholesterol absorption inhibitors such as, bileacid-binding substances such as, inhibitors of ileac bile acidtransport, MTP inhibitors, or HDL-raising compounds such as CETPinhibitors or ABC1 regulators.

Therapeutic agents for the treatment of overweight and/or obesity arefor example antagonists of the cannabinoid1 receptor, MCH-1 receptorantagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists,β3-agonists, leptin or leptin mimetics, agonists of the 5HT2c receptor.

Therapeutic agents for the treatment of high blood pressure, chronicheart failure and/or atherosclerosis are for example A-II antagonists orACE inhibitors, ECE inhibitors, diuretics, β-blockers, Ca-antagonists,centrally acting antihypertensives, antagonists of thealpha-2-adrenergic receptor, inhibitors of neutral endopeptidase,thrombocyte aggregation inhibitors and others or combinations thereofare suitable. Angiotensin II receptor antagonists are preferably usedfor the treatment or prevention of high blood pressure and complicationsof diabetes, often combined with a diuretic such as hydrochlorothiazide.

The dosage for the combination partners mentioned above is usually 1/5of the lowest dose normally recommended up to 1/1 of the normallyrecommended dose.

Preferably, compounds of the present invention and/or pharmaceuticalcompositions comprising a compound of the present invention optionallyin combination with one or more additional therapeutic agents areadministered in conjunction with exercise and/or a diet.

Therefore, in another aspect, this invention relates to the use of acompound according to the invention in combination with one or moreadditional therapeutic agents described hereinbefore and hereinafter forthe treatment of diseases or conditions which may be affected or whichare mediated by the activation of the G-protein-coupled receptor GPR40,in particular diseases or conditions as described hereinbefore andhereinafter.

In yet another aspect the present invention relates a method fortreating a disease or condition mediated by the activation of theG-protein-coupled receptor GPR40 in a patient that includes the step ofadministering to the patient, preferably a human, in need of suchtreatment a therapeutically effective amount of a compound of thepresent invention in combination with a therapeutically effective amountof one or more additional therapeutic agents described in hereinbeforeand hereinafter,

The use of the compound according to the invention in combination withthe additional therapeutic agent may take place simultaneously or atstaggered times.

The compound according to the invention and the one or more additionaltherapeutic agents may both be present together in one formulation, forexample a tablet or capsule, or separately in two identical or differentformulations, for example as a so-called kit-of-parts.

Consequently, in another aspect, this invention relates to apharmaceutical composition which comprises a compound according to theinvention and one or more additional therapeutic agents describedhereinbefore and hereinafter, optionally together with one or more inertcarriers and/or diluents.

Other features and advantages of the present invention will becomeapparent from the following more detailed Examples which illustrate, byway of example, the principles of the invention.

EXAMPLES

The terms “ambient temperature” and “room temperature” are usedinterchangeably and designate a temperature of about 20° C.

Preliminary Remarks:

As a rule, ¹H-NMR and/or mass spectra have been obtained for thecompounds prepared. The R_(f) values are determined using Merck silicagel 60 F₂₅₄ plates and UV light at 254 nm.

Analytical HPLC parameters employed for characterization of products(TFA denotes trifluoroacetic acid):

Method: 1 Device: Agilent 1200 with DA and MS detector Column: XBridgeC18, 3 × 30 mm, 2.5 μm Column Supplier: Waters Gradient/ % SolventSolvent [H₂O, % Solvent Flow Temperature Time [min] 0.1% TFA] [Methanol][mL/min] [° C.] 0.0 95 5 2.2 60 0.05 95 5 2.2 60 1.40 0 100 2.2 60 1.800 100 2.2 60 Method: 2 Device: Agilent 1200 with DA and MS detectorColumn: XBridge C18, 3 × 30 mm, 2.5 μm Column Supplier: Waters Gradient/% Solvent Solvent [H₂O, % Solvent Flow Temperature Time [min] 0.1% TFA][CH₃CN] [mL/min] [° C.] 0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0 100 2.260 1.25 0 100 3 60 1.40 0 100 3 60 Method: 3 Device: Agilent 1200 withDA and MS detector Column: XBridge C18, 3 × 30 mm, 2.5 μm ColumnSupplier: Waters Gradient/ % Solvent Solvent [H₂O, % Solvent FlowTemperature Time [min] 0.1% TFA] [CH₃CN] [mL/min] [° C.] 0.00 50 50 2.260 0.20 50 50 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60Method: 4 Device: Agilent 1200 with DA and MS detector Column: Sunfire,3 × 30 mm, 2.5 μm Column Supplier: Waters Gradient/ % Solvent Solvent[H₂O, % Solvent Flow Temperature Time [min] 0.1% TFA] [CH₃CN] [mL/min][° C.] 0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0 100 2.2 60 1.25 0 100 360 1.40 0 100 3 60 Method: 5 Device: Agilent 1100 with DA and MSdetector Column: XBridge C18, 4.6 × 30 mm, 3.5 μm Column Supplier:Waters Gradient/ % Solvent Solvent [H₂O, 0.1% % Solvent Flow TemperatureTime [min] HCOOH] [Methanol] [mL/min] [° C.] 0.0 50 50 4 60 0.15 50 50 460 1.7 0 100 4 60 2.25 0 100 4 60 Method: 6 Device: Agilent 1200 with DAand MS detector Column: XBridge C18, 3.0 × 30 mm, 2.5 μm ColumnSupplier: Waters Gradient/ % Solvent Solvent [H₂O, 0.1% % Solvent FlowTemperature Time [min] NH₄OH] [Acetonitrile] [mL/min] [° C.] 0.0 97.03.0 2.2 60 0.2 97.0 3.0 2.2 60 1.2 0.0 100.0 2.2 60 1.25 0.0 100.0 3.060 1.4 0.0 100.0 3.0 60 Method: 7 Device: Agilent 1200 with DA and MSdetector Column: XBridge C18, 3 × 30 mm, 2.5 μm Column Supplier: WatersGradient/ % Solvent Solvent [H₂O, % Solvent Flow Temperature Time [min]0.1% NH₃] [CH₃CN] [mL/min] [° C.] 0.00 50 50 2.2 60 0.20 50 50 2.2 601.20 0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60 Method: 8 Device:Agilent 1200 with DA and MS detector Column: Sunfire C18, 3 × 30 mm, 2.5μm Column Supplier: Waters Gradient/ % Solvent Solvent [H₂O, % SolventFlow Temperature Time [min] 0.1% TFA] [CH₃CN] [mL/min] [° C.] 0.00 97 32.2 60 0.20 97 3 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 360 Method: 9 Device: Agilent 1200 with DA and MS detector Column:Sunfire, 3 × 30 mm, 2.5 μm Column Supplier: Waters Gradient/ % SolventSolvent [H₂O, % Solvent Flow Temperature Time [min] 0.1% TFA] [CH₃CN][ml/min] [° C.] 0.00 50 50 2.2 60 0.20 50 50 2.2 60 1.20 0 100 2.2 601.25 0 100 3 60 1.40 0 100 3 60

The Examples that follow are intended to illustrate the presentinvention without restricting it:

Intermediate 1{(S)-6-[(R)-4-benzyl-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

Step 1: 4-bromo-5-hydroxy-indan-1-one

Sodium methanethiolate (2.00 g) is added to a microwave vial chargedwith a stir bar, 4-bromo-5-methoxy-indan-1-one (1.58 g), andN,N-dimethylformamide (10 mL). The vial is sealed and the mixture isheated to 130° C. and stirred at this temperature for 2 h. After coolingto room temperature, the mixture is partitioned between ethyl acetateand 1 N aqueous HCl solution. The aqueous phase is separated andextracted with ethyl acetate. The combined organic phases are washedwith brine and dried (MgSO₄). The solvents are evaporated and theresidue is triturated with diethylether. The precipitate is filtered offand dried in vacuo to give the title compound. LC (method 1): t_(R)=0.84min; Mass spectrum (ESI⁺): m/z=227/229 (Br) [M+H]⁺.

Step 2: trifluoro-methanesulfonic acid 4-bromo-1-oxo-indan-5-yl ester

Trifluoromethanesulfonic anhydride (4.0 mL) is added dropwise to asolution of 4-bromo-5-hydroxy-indan-1-one (5.0 g) and2,6-dimethylpyridine (5.1 mL) in dichloromethane (50 mL) cooled to 0° C.The cooling bath is removed and the mixture is stirred for 2 h at roomtemperature. The solution is partitioned between saturated aqueous NH₄Clsolution and dichloromethane. The organic phase is separated, washedwith brine, dried (MgSO₄), and concentrated. The residue ischromatographed on silica gel (cyclohexane/ethyl acetate 99:1→50:50) togive the title compound. LC (method 2): t_(R)=1.08 min; Mass spectrum(ESI⁺): m/z=359/361 (Br) [M+H]⁺.

Step 3: 4-bromo-1-oxo-indan-5-carbonitrile

Zn(CN)₂ (0.60 g) and 1,1′-bis(diphenylphosphino)-ferrocene (0.92 g) areadded to a solution of trifluoro-methanesulfonic acid4-bromo-1-oxo-indan-5-yl ester (5.90 g) in N,N-dimethylformamide (30 mL)at room temperature. The mixture is purged with Ar for 5 min prior toaddition of tris(dibenzylideneacetone)dipalladium(0) (760 mg). Themixture is heated to 70° C. and stirred at this temperature for 1 h.After cooling to room temperature, ethyl acetate is added and theresulting mixture is washed with water and brine. The organic phase isdried (MgSO₄) and concentrated. The residue is chromatographed on silicagel (cyclohexane/ethyl acetate 99:1→50:50) to give the title compound.LC (method 2): t_(R)=0.88 min; Mass spectrum (ESI⁻): m/z=234/236 (Br)[M−H]⁻.

Step 4: (S)-4-bromo-1-hydroxy-indan-5-carbonitrile

Formic acid (1.8 mL) is added to a solution of triethylamine (5.7 mL) indichloromethane (30 mL) chilled in an ice bath.4-Bromo-1-oxo-indan-5-carbonitrile (3.20 g) is added and the flask ispurged with Ar for 5 min.Chloro{[(1S,2S)-(−)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido}-(mesitylene)ruthenium(II)(0.40 g; alternatively, the catalyst is formed in situ fromN-[(1S,2S)-2-amino-1,2-diphenylethyl]-4-methylbenzenesulfonamide anddichloro(p-cymene)-ruthenium(II) dimer) is added and the mixture isstirred at room temperature for 2 h. The mixture is diluted withdichloromethane and washed with water and brine and dried (MgSO₄). Thesolvent is evaporated and the residue is chromatographed on silica gel(cyclohexane/ethyl acetate 80:20→20:80) to give the title compound. LC(method 2): t_(R)=0.84 min; Mass spectrum (ESI⁺): m/z=260/262 (Br)[M+Na]⁺.

Step 5:{(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

A solution of di-tert-butyl azodicarboxylate (3.30 g) in tetrahydrofuran(5 mL) is added dropwise over 45 min to a solution of(S)-(6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester(for preparation see WO 2008001931; 2.10 g),(S)-4-bromo-1-hydroxy-indan-5-carbonitrile (2.40 g) andtri-n-butyl-phosphine (3.8 mL) in tetrahydrofuran (25 mL) at −10° C. Theresulting solution is stirred for 30 min and then diluted with ethylacetate. The resulting solution is washed with water and brine and dried(MgSO₄). The solvent is evaporated and the residue is chromatographed onsilica gel (cyclohexane/ethyl acetate 99:1→70:30) to give the titlecompound. LC (method 2): t_(R)=1.15 min; Mass spectrum (ESI⁺):m/z=428/430 (Br) [M+H]⁺.

Step 6:{(S)-6-[(R)-4-benzyl-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

A flask charged with a stir bar,{(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester (0.10 g), and tetrahydrofuran (1 mL) is purged with Arfor 5 min. Benzylzinc bromide (0.5 mol/L in tetrahydrofuran, 1.5 mL) andtetrakis(triphenylphosphine)palladium (30 mg) are added and the mixtureis heated to 60° C. The mixture is stirred at 60° C. overnight and thencooled to room temperature. Aqueous NH₄Cl solution is added and theresulting mixture is extracted with ethyl acetate. The combined extractsare dried (MgSO₄) and concentrated. The crude title compound is usedwithout further purification. LC (method 4): t_(R)=1.23 min; Massspectrum (ESI⁺): m/z=462 [M+Na]⁺.

Intermediate 2{(S)-6-[(R)-4-Bromo-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

Step 1: (S)-4-bromo-7-fluoro-indan-1-ol

The title compound is prepared from 4-bromo-7-fluoro-indan-1-onefollowing a procedure analogous to that described in Step 4 ofIntermediate 1. LC (method 1): t_(R)=1.04 min; Mass spectrum (ESI⁺):m/z=213/215 (Br) [M+H-H₂O]⁺.

Step 2:{(S)-6-[(R)-4-bromo-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

A solution of di-tert-butyl azodicarboxylate (18.0 g) in tetrahydrofuran(80 mL) is added dropwise over 45 min to a solution of[(S)-6-hydroxy-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester(for preparation see WO 2008001931; 11.0 g),(S)-4-bromo-7-fluoro-indan-1-ol (11.95 g), and tri-n-butyl-phosphine(19.3 mL) in tetrahydrofuran (320 mL) at −10° C. The resulting solutionis stirred for 30 min and then partitioned between saturated aqueousNaHCO₃ solution and dichloromethane. The aqueous phase is separated andextracted with dichloromethane. The combined organic phases are dried(MgSO₄) and concentrated. The residue is chromatographed on silica gel(cyclohexane/ethyl acetate 90:10→70:30) to give the title compound. LC(method 1): t_(R)=1.41 min; Mass spectrum (ESI⁺): m/z=421/423 (Br)[M+H]⁺.

Intermediate 3{(S)-6-[(R)-4-Bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

Step 1: 2-bromo-1-iodo-3-trifluoromethyl-benzene

An ice-cold solution of NaNO₂ (0.15 g) in water (0.5 mL) is added to amixture of 2-bromo-3-trifluoromethyl-aniline (0.48 g), concentratedH₂SO₄ (2 mL), and water (1.8 mL) at ca. 5° C. The mixture is stirred inthe cooling bath for 20 min and then poured into a solution of KI (0.56g) and I₂ (0.56 g) in water (0.5 mL). After ceasing of gas evolution,the mixture is heated to 40° C. and stirred at this temperature for 1 h.The mixture is cooled to room temperature and aqueous Na₂SO₃ solution isadded. The resulting mixture is extracted with ethyl acetate and thecombined extracts are dried (Na₂SO₄) and concentrated. The solvent isevaporated and the residue is chromatographed (cyclohexane/ethyl acetate95:5→90:10) to give the title compound.

Step 2: 3-(2-bromo-3-trifluoromethyl-phenyl)-propionic acid methyl ester

A microwave suited vial charged with a stir bar,2-bromo-1-iodo-3-trifluoromethyl-benzene (4.04 g),N,N-diisopropylethylamine (4.0 mL), acrolein dimethyl acetal (1.76 g),tetrabutylammonium chloride (3.30 g), and dry N,N-dimethylformamide (10mL) is purged with Ar for 5 min. Palladium(II) acetate (0.13 g) isadded, the vial is sealed, and the mixture is stirred for 20 min at 120°C. in a microwave oven. After cooling to room temperature, the mixtureis diluted with ethyl acetate and the resulting mixture is washed with 1M aqueous HCl solution and brine and dried (Na₂SO₄). The solvent isevaporated and the residue is chromatographed (cyclohexane/ethyl acetate90:10) to give the title compound.

Step 3: 3-(2-bromo-3-trifluoromethyl-phenyl)-propionic acid

The title compound is prepared from3-(2-bromo-3-trifluoromethyl-phenyl)-propionic acid methyl esterfollowing a procedure analogous to that described in Example 1. LC(method 5): t_(R)=0.93 min; Mass spectrum (ESI⁻): m/z=295/297 (Br)[M−H]⁻.

Step 4: 4-bromo-5-trifluoromethyl-indan-1-one

3-(2-Bromo-3-trifluoromethyl-phenyl)-propionic acid (3.25 g) intrifluoromethane-sulfonic acid (30 ml) is stirred at 75° C. for 2.5 h.After cooling to room temperature, the mixture is poured into water andthe resulting mixture is extracted with ethyl acetate. The combinedorganic extract is washed with aqueous NaHCO₃ solution, dried (Na₂SO₄),and concentrated. The residue is chromatographed on silica gel(cyclohexane/ethyl acetate 90:10→80:20) to afford the title compound. LC(method 5): t_(R)=0.90 min.

Step 5: (S)-4-bromo-5-trifluoromethyl-indan-1-ol

The title compound is prepared from4-bromo-5-trifluoromethyl-indan-1-one following a procedure analogous tothat described in Step 4 of Intermediate 1. LC (method 5): t_(R)=0.94min; Mass spectrum (ESI⁻): m/z=279/281 (Br) [M−H]⁻.

Step 6:{(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

The title compound is prepared from[(S)-6-hydroxy-2,3-dihydro-benzofuran-3-yl]-acetic acid methyl ester and(S)-4-bromo-5-trifluoromethyl-indan-1-ol following a procedure analogousto that described in Step 2 of Intermediate 2. LC (method 5): t_(R)=1.62min; Mass spectrum (ESI⁺): m/z=471/473 (Br) [M+H]⁺.

Intermediate 4{(S)-6-[(R)-4-(6-Chloro-pyridin-3-ylmethyl)-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

The title compound is prepared from{(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester and 6-chloro-pyridin-3-ylmethylzinc chloride followinga procedure analogous to that described in Step 6 of Intermediate 1. LC(method 4): t_(R)=1.17 min; Mass spectrum (ESI⁺): m/z=475/477 [M+H]⁺.

Intermediate 5{(S)-6-[(R)-5-cyano-4-(3-methoxy-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

The title compound is prepared from{(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester and 3-methoxy-benzylzinc chloride following aprocedure analogous to that described in Step 6 of Intermediate 1. LC(method 4): t_(R)=1.22 min; Mass spectrum (ESI⁺): m/z=492 [M+Na]⁺.

Intermediate 6{(S)-6-[(R)-5-cyano-4-(4-methoxy-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

The title compound is prepared from{(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester and 4-methoxy-benzylzinc chloride following aprocedure analogous to that described in Step 6 of Intermediate 1. LC(method 4): t_(R)=1.22 min; Mass spectrum (ESI⁺): m/z=492 [M+Na]⁺.

Intermediate 7{(S)-6-[(R)-5-cyano-4-(2,6-dimethyl-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

A flask charged with a stir bar and anhydrous LiCl (49 mg) is heated to180° C. under high vacuum (ca. 1 mbar). After 30 min the flask is cooledto room temperature, filled with Ar, and Zn powder (84 mg) is addedunder Ar atmosphere. The flask is reevacuated (ca. 1 mbar) and heated to180° C. After another 30 min the flask is cooled to room temperature andfilled with Ar again. Tetrahydrofuran (dry, 0.5 mL) is added and the Znis activated with 1,2-dibromoethane (2 μL) and trimethylsilyl chloride(1.5 μL) (for comparison see e.g. Synthesis 2009, 681-6). A solution of2,6-dimethylbenzyl bromide (0.23 g) in tetrahydrofuran (dry, 2 mL) isadded dropwise. The mixture is stirred for 30 min prior to addition of{(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester (0.10 g) in tetrahydrofuran (dry, 2 mL) and[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II)dichloride (Pd-PEPPSI-IPr, 20 mg). The mixture is heated to 60° C. andstirred at this temperature overnight. After cooling to roomtemperature, aqueous NH₄Cl solution is added and the resulting mixtureis extracted with ethyl acetate. The combined extracts are dried (MgSO₄)and concentrated. The residue is purified by HPLC on reversed phase(MeCN/water/NH₄OH) to give the title compound. LC (method 4): t_(R)=1.28min; Mass spectrum (ESI⁺): m/z=468 [M+H]⁺.

Intermediate 8{(S)-6-[(R)-5-cyano-4-(2-methyl-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

The title compound is prepared from{(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester and 2-methyl-benzylzinc chloride following a procedureanalogous to that described in Step 6 of Intermediate 1. LC (method 4):t_(R)=1.22 min; Mass spectrum (ESI⁺): m/z=476 [M+Na]⁺.

Intermediate 9{(S)-6-[(R)-5-cyano-4-(4-methylsulfanyl-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

The title compound is prepared from{(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester and 4-methylsulfanyl-benzyl bromide following aprocedure analogous to that described for Intermediate 7. LC (method 4):t_(R)=1.12 min; Mass spectrum (ESI⁺): m/z=508 [M+Na]⁺.

Intermediate 10{(S)-6-[(R)-5-cyano-4-(3-cyano-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

The title compound is prepared from{(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester and 3-cyano-benzylzinc bromide following a procedureanalogous to that described in Step 6 of Intermediate 1. LC (method 4):t_(R)=1.18 min; Mass spectrum (ESI⁺): m/z=487 [M+Na]⁺.

Intermediate 11{(S)-6-[(R)-4-benzyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

The title compound is prepared from{(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester and benzylzinc bromide following a procedure analogousto that described in Step 6 of Intermediate 1. LC (method 3): t_(R)=0.94min; Mass spectrum (ESI⁺): m/z=505 [M+Na]⁺.

Intermediate 12{(S)-6-[(R)-4-(4-Acetoxy-benzyl)-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

The title compound is prepared from{(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester and 4-acetoxy-benzyl bromide following a procedureanalogous to that described for Intermediate 7.

Intermediate 13{(S)-6-[(R)-7-Fluoro-4-(4-methoxy-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

The title compound is prepared from{(S)-6-[(R)-4-bromo-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester (84 mg), 4-methoxy-benzylzinc chloride (0.5 mol/L intetrahydrofuran, 1.2 mL) and tetrakis(triphenylphosphine)-palladium (23mg). Degassed tetrahydrofuran (1 mL) is added under Ar atmosphere, andthe mixture is heated to 60° C. and shaken at this temperatureovernight. After cooling to room temperature, the mixture is acidifiedwith 4 N aqueous hydrochloric acid (1 mL) and then neutralized withsaturated aqueous ammonia solution. The organic phase is separated,diluted with N,N-dimethylformamide (1 mL), and purified by HPLC onreversed phase (MeCN/water) to give the title compound. LC (method 6):t_(R)=1.16 min.

Intermediate 14{(S)-6-[(R)-7-Fluoro-4-(3-methoxy-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

The title compound is prepared from{(S)-6-[(R)-4-bromo-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester (84 mg), 3-methoxy-benzylzinc chloride (0.5 mol/L intetrahydrofuran, 1.2 mL) and tetrakis(triphenylphosphine)-palladium (23mg). Degassed tetrahydrofuran (1 mL) is added under Ar atmosphere, andthe mixture is heated to 60° C. and shaken at this temperatureovernight. The mixture is acidified with 4 N aqueous hydrochloric acid(1 mL) and then neutralized with saturated aqueous ammonia solution. Theorganic phase is separated, diluted with N,N-dimethylformamide (1 mL),and purified by HPLC on reversed phase (MeCN/water) to give the titlecompound. LC (method 6): t_(R)=1.17 min.

Intermediate 15{(S)-6-[(R)-(6-Chloro-pyridin-3-ylmethyl)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

The title compound is prepared from{(S)-6-[(R)-4-bromo-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester (84 mg), (2-chloro-pyrid-5-yl)methylzinc chloride (0.5moL/L in tetrahydrofuran, 1.2 mL) andtetrakis(triphenylphosphine)palladium (23 mg). Degassed tetrahydrofuran(1 mL) is added under Ar atmosphere, and the mixture is heated to 60° C.and shaken at this temperature overnight. The mixture is acidified with4 N aqueous hydrochloric acid (1 mL) and then neutralized with saturatedaqueous ammonia solution. The organic phase is separated, diluted withN,N-dimethylformamide (1 mL), and purified by HPLC on reversed phase(MeCN/water) to give the title compound. LC (method 6): t_(R)=1.04 min.

Intermediate 16{(S)-6-[(R)-4-Benzyl-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

The title compound is prepared from{(S)-6-[(R)-4-bromo-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester (84 mg), benzylzinc bromide (0.5 mol/L intetrahydrofuran, 1.2 ml) and tetrakis(triphenylphosphine)palladium (23mg). Degassed tetrahydrofuran (1 mL) is added under Ar atmosphere, andthe mixture is heated to 60° C. and shaken at this temperatureovernight. The reaction mixture is acidified with 4 N aqueoushydrochloric acid (1 mL) and then neutralized with saturated aqueousammonia solution. The organic phase is separated, diluted withN,N-dimethylformamide (1 mL), and purified by HPLC on reversed phase(MeCN/water) to give the title compound. LC (method 6): t_(R)=1.19 min.

Intermediate 17{(S)-6-[(R)-4-(4-Methylsulfanyl-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

The title compound is prepared from{(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester and 4-methylsulfanyl-benzyl bromide following aprocedure analogous to that described for Intermediate 7.

Intermediate 18{(S)-6-[(R)-4-(4-Methylsulfonyl-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

3-Chloro-peroxybenzoic acid (70%, 76 mg) is added to a solution of{(S)-6-[(R)-4-(4-methylsulfanyl-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester (65 mg) in dichloromethane (2 mL) at room temperature.The solution is stirred at room temperature for 3 h and is thenconcentrated. The residue is taken up in methanol and chromatographed(HPLC, acetonitrile/water) to give the title compound. LC (method 3):t_(R)=0.65 min; Mass spectrum (ESI⁺): m/z=583 [M+Na]⁺.

Intermediate 19{(S)-6-[(R)-4-(3,5-Difluoro-benzyl)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

The title compound is prepared from{(S)-6-[(R)-4-bromo-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester and 3,5-difluoro-benzylzinc bromide following aprocedure analogous to that described in Step 6 of Intermediate 1;[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II)dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 9):t_(R)=0.91 min; Mass spectrum (ESI⁺): m/z=491 [M+Na]⁺.

Intermediate 20{(S)-6-[(R)-4-(2,6-Difluoro-benzyl)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

The title compound is prepared from{(S)-6-[(R)-4-bromo-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester and 2,6-difluoro-benzylzinc bromide following aprocedure analogous to that described in Step 6 of Intermediate 1;[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II)dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 9):t_(R)=0.91 min; Mass spectrum (ESI⁺): m/z=491 [M+Na]⁺.

Intermediate 21{(S)-6-[(R)-4-(4-Cyano-benzyl)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

The title compound is prepared from{(S)-6-[(R)-4-bromo-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester and 4-cyano-benzylzinc bromide following a procedureanalogous to that described in Step 6 of Intermediate 1;[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II)dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 9):t_(R)=0.74 min; Mass spectrum (ESI⁺): m/z=458 [M+H]⁺.

Intermediate 22{(S)-6-[(R)-4-(2,4-Difluoro-benzyl)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

The title compound is prepared from{(S)-6-[(R)-4-bromo-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester and 2,4-difluoro-benzylzinc bromide following aprocedure analogous to that described in Step 6 of Intermediate 1;[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II)dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 9):t_(R)=0.91 min; Mass spectrum (ESI⁺): m/z=491 [M+Na]⁺.

Intermediate 23{(S)-6-[(R)-5-Cyano-4-(2-fluoro-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

The title compound is prepared from{(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester and 2-fluoro-benzyl bromide following a procedureanalogous to that described for Intermediate 7. LC (method 6):t_(R)=1.19 min; Mass spectrum (ESI⁺): m/z=458 [M+H]⁺.

Intermediate 24{(S)-6-[(R)-5-Cyano-4-(4-fluoro-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

The title compound is prepared from{(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester and 4-fluoro-benzyl bromide following a procedureanalogous to that described for Intermediate 7. LC (method 6):t_(R)=1.18 min; Mass spectrum (ESI⁺): m/z=458 [M+H]⁺.

Intermediate 25{(S)-6-[(R)-5-Cyano-4-(3-fluoro-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

The title compound is prepared from{(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester and 3-fluoro-benzylzinc bromide following a procedureanalogous to that described in Step 6 of Intermediate 1;[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II)dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 4):t_(R)=1.22 min; Mass spectrum (ESI⁺): m/z=458 [M+H]⁺.

Intermediate 26{(S)-6-[(R)-4-(4-Acetoxy-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

The title compound is prepared from{(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester and 4-acetoxy-benzyl bromide following a procedureanalogous to that described for Intermediate 7. LC (method 8):t_(R)=1.27 min; Mass spectrum (ESI⁺): m/z=541 [M+H]⁺.

Intermediate 27{(S)-6-[(R)-4-(4-Hydroxy-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

A mixture of{(S)-6-[(R)-4-(4-acetoxy-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester (0.19 g), K₂CO₃ (0.08 g), and methanol (5 ml) isstirred at room temperature for 2 h. The solution is neutralized with 1N aqueous HCl solution and concentrated. Water is added to the residue,and the resulting mixture is extracted with ethyl acetate. The combinedextract is dried (MgSO₄) and concentrated. The residue ischromatographed on silica gel (cyclohexane/ethyl acetate) to give thetitle compound. LC (method 8): t_(R)=1.22 min; Mass spectrum (ESI⁺):m/z=521 [M+Na]⁺.

Intermediate 28{(S)-6-[(R)-4-(2,4-Difluoro-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

The title compound is prepared from{(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester and 2,4-difluoro-benzylzinc bromide following aprocedure analogous to that described in Step 6 of Intermediate 1;[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II)dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 3):t_(R)=0.98 min; Mass spectrum (ESI⁺): m/z=541 [M+Na]⁺.

Intermediate 29{(S)-6-[(R)-4-(3-Methoxy-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

The title compound is prepared from{(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester and 3-methoxy-benzylzinc bromide following a procedureanalogous to that described in Step 6 of Intermediate 1;[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II)dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 8):t_(R)=1.30 min; Mass spectrum (ESI⁺): m/z=535 [M+Na]⁺.

Intermediate 30{(S)-6-[(R)-5-Cyano-4-(2,6-difluoro-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

The title compound is prepared from{(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester and 2,6-difluoro-benzylzinc bromide following aprocedure analogous to that described in Step 6 of Intermediate 1;[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II)dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 4):t_(R)=1.22 min; Mass spectrum (ESI⁺): m/z=476 [M+H]⁺.

Intermediate 31{(S)-6-[(R)-4-(3-Fluoro-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

The title compound is prepared from{(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester and 3-fluoro-benzylzinc chloride following a procedureanalogous to that described in Step 6 of Intermediate 1;[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II)dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 7):t_(R)=0.98 min; Mass spectrum (ESI⁺): m/z=523 [M+Na]⁺.

Intermediate 32{(S)-6-[(R)-4-(4-Fluoro-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

The title compound is prepared from{(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester and 4-fluoro-benzylzinc chloride following a procedureanalogous to that described in Step 6 of Intermediate 1;[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II)dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 6):t_(R)=1.28 min; Mass spectrum (ESI⁺): m/z=501 [M+H]⁺.

Intermediate 33{(S)-6-[(R)-4-(2-Fluoro-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

The title compound is prepared from{(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester and 2-fluoro-benzylzinc chloride following a procedureanalogous to that described in Step 6 of Intermediate 1;[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II)dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 6):t_(R)=1.29 min; Mass spectrum (ESI⁺): m/z=501 [M+H]⁺.

Intermediate 34{(S)-6-[(R)-5-Cyano-4-(2,3-difluoro-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

The title compound is prepared from{(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester and 2,3-difluoro-benzyl bromide following a procedureanalogous to that described for Intermediate 7. LC (method 4):t_(R)=1.25 min; Mass spectrum (ESI⁺): m/z=476 [M+H]⁺.

Intermediate 35{(S)-6-[(R)-4-(4-Methoxy-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

Iodomethane (8 μL) is added to a mixture of{(S)-6-[(R)-4-(4-hydroxy-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester (30 mg), K₂CO₃ (15 mg), and N,N-dimethylformamide (1mL) at room temperature. The mixture is stirred at room temperatureovernight. The mixture is filtered and then chromatographed (HPLC;acetonitrile/water) to give the title compound. LC (method 6):t_(R)=1.26 min; Mass spectrum (ESI⁺): m/z=535 [M+Na]⁺.

Intermediate 36{(S)-6-[(R)-4-(3-Cyano-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

The title compound is prepared from{(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester and 3-cyano-benzylzinc bromide following a procedureanalogous to that described in Step 6 of Intermediate 1;[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II)dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 6):t_(R)=1.23 min; Mass spectrum (ESI⁺): m/z=508 [M+H]⁺.

Intermediate 37{(S)-6-[(R)-4-(2-Methyl-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

The title compound is prepared from{(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester and 2-methyl-benzylzinc chloride following a procedureanalogous to that described in Step 6 of Intermediate 1;[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II)dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 6):t_(R)=1.29 min; Mass spectrum (ESI⁺): m/z=497 [M+H]⁺.

Intermediate 38{(S)-6-[(R)-4-(2-Cyano-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

The title compound is prepared from{(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester and 2-cyano-benzylzinc bromide following a procedureanalogous to that described in Step 6 of Intermediate 1;[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II)dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 6):t_(R)=1.23 min; Mass spectrum (ESI⁺): m/z=508 [M+H]⁺.

Intermediate 39{(S)-6-[(R)-4-(4-Chloro-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

The title compound is prepared from{(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester and 4-chloro-benzylzinc chloride following a procedureanalogous to that described in Step 6 of Intermediate 1;[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II)dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 3):t_(R)=1.01 min.

Intermediate 40{(S)-6-[(R)-5-Trifluoromethyl-4-vinyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

A flask charged with a stir bar,{(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester (1.00 g), vinylboronic acid pinacol ester (0.39 g),K₃PO₄ (1.80 g), toluene (8 mL) and water (0.8 mL) is purged with Ar for10 min. Palladium(II) acetate (24 mg) anddicyclohexyl-(2′,6′-dimethoxybiphenyl-2-yl)-phosphine (S-Phos, 87 mg)are added, the flask is sealed, and the mixture is heated to 100° C. Themixture is stirred at this temperature overnight. After cooling to roomtemperature, water is added and the mixture is extracted with ethylacetate. The combined extract is washed with brine, dried(charcoal/Na₂SO₄), and concentrated. The crude product is submitted tothe next reaction step without further purification. LC (method 2):t_(R)=1.26 min; Mass spectrum (ESI⁺): m/z=457 [M+Na]⁺.

Intermediate 41{(S)-6-[(R)-4-Formyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

NaIO₄ (1.80 g) and OsO₄ (4% in water, 50 μL) are added to a mixture of{(S)-6-[(R)-5-trifluoromethyl-4-vinyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester (1.25 g), tetrahydrofuran (16 mL), and water (4 mL) atroom temperature. The mixture is stirred at 50° C. overnight. Aftercooling to room temperature, water is added and the mixture is extractedwith ethyl acetate. The combined extract is washed with brine, dried(Na₂SO₄), and concentrated. The residue is chromatographed on silica gel(cyclohexane/ethyl acetate) to give the title compound. LC (method 2):t_(R)=1.19 min; Mass spectrum (ESI⁺): m/z=421 [M+H]⁺.

Intermediate 42{(S)-6-[(R)-4-Hydroxymethyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

NaBH₄ (18 mg) is added to a solution of{(S)-6-[(R)-4-formyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester (0.20 g) in tetrahydrofuran (4 mL) and water (1 mL) atroom temperature. The mixture is stirred at room temperature for 30 min.1 N aqueous HCl solution is added and the mixture is extracted withethyl acetate. The combined extract is washed with brine, dried(Na₂SO₄), and concentrated to give the title compound. The crude productis submitted to the next reaction step without further purification. LC(method 2): t_(R)=1.19 min; Mass spectrum (ESI⁺): m/z=421 [M+H]⁺.

Intermediate 43{(S)-6-[(R)-4-Bromomethyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

Methylsulfonyl bromide (0.96 mL) is added to a solution of{(S)-6-[(R)-4-hydroxymethyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester (2.00 g) and triethylamine (1.98 mL) indichloromethane (20 mL) chilled in an ice bath. The cooling bath isremoved, and the solution is stirred at room temperature overnight. Moredichloromethane is added, and the resulting solution is washed withaqueous NaHCO₃ solution and brine, dried (Na₂SO₄), and concentrated. Theresidue is chromatographed on silica gel (cyclohexane/ethyl acetate) togive the title compound. LC (method 2): t_(R)=1.24 min.

Intermediate 44{(S)-6-[(R)-4-(2-Methoxy-pyridin-5-yl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

A flask charged with a stir bar, 2 M aqueous Na₂CO₃ solution (0.13 mL),{(S)-6-[(R)-4-bromomethyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester (50 mg), 2-methoxy-pyridine-5-boronic acid (16 mg),and N,N-dimethylformamide (1 mL) is purged with Ar for 5 min.[1,1′-Bis(diphenylphosphino)-ferrocene]-dichloropalladium(II)*CH₂Cl₂complex (5 mg) is added and the mixture is heated to 65° C. The mixtureis stirred at 65° C. overnight and then cooled to room temperature.Water is added and the resulting mixture is extracted with ethylacetate. The combined extract is washed with brine, dried (MgSO₄), andconcentrated. The residue is chromatographed (HPLC;acetonitrile/water/ammonia) to give the title compound. LC (method 2):t_(R)=1.23 min; Mass spectrum (ES⁺): m/z=514 [M+H]⁺.

Intermediate 45{(S)-6-[(R)-4-(2-Fluoro-pyridin-5-yl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

A flask charged with a stir bar, 2 M aqueous Na₂CO₃ solution (85 μL),{(S)-6-[(R)-4-bromomethyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester (40 mg), 2-fluoro-pyridine-5-boronic acid (12 mg),ethanol (0.25 mL), and toluene (1 mL) is purged with Ar for 5 min.Tetrakis(triphenylphosphine)-palladium(0) (5 mg) is added and themixture is heated to 80° C. The mixture is stirred at 80° C. overnightand then cooled to room temperature. Water is added and the resultingmixture is extracted with ethyl acetate. The combined extract is washedwith brine, dried (MgSO₄), and concentrated. The residue ischromatographed on silica gel (cyclohexane/ethyl acetate) to give thetitle compound. LC (method 2): t_(R)=1.00 min; Mass spectrum (ESI⁺):m/z=502 [M+H]⁺.

Intermediate 46{(S)-6-[(R)-4-(2,5-Dimethoxy-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester

The title compound is prepared from{(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester and 2,5-dimethoxy-benzylzinc chloride following aprocedure analogous to that described in Step 6 of Intermediate 1;[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II)dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 3):t_(R)=0.94 min; Mass spectrum (ESI⁺): m/z=565 [M+Na]⁺.

Example 1{(S)-6-[(R)-4-Benzyl-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid

1 M aqueous NaOH solution (0.60 mL) is added to a solution of{(S)-6-[(R)-4-benzyl-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester (0.10 g) in methanol (3 mL) at room temperature. Themixture is stirred at 40° C. for 1 h. The mixture is diluted with waterand neutralized with 1 M aqueous HCl solution. The resulting mixture isextracted with ethyl acetate, and the combined extract is washed withbrine and dried (MgSO₄). The solvent is evaporated and the residue ischromatographed on silica gel (cyclohexane/ethyl acetate 50:50→0:100) togive the title compound. In case the product is insufficiently pureafter this procedure the product is submitted to HPLC on reversed phase(MeCN/water). LC (method 4): t_(R)=1.14 min; Mass spectrum (ESI⁺):m/z=424 [M+H]⁺.

Example 2{(S)-6-[(R)-4-(6-Chloro-pyridin-3-ylmethyl)-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid

The title compound is prepared from{(S)-6-[(R)-4-(6-chloro-pyridin-3-ylmethyl)-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester following a procedure analogous to that described forExample 1. LC (method 4): t_(R)=1.07 min; Mass spectrum (ESI⁺):m/z=461/463 (Cl) [M+H]⁺.

Example 3{(S)-6-[(R)-5-Cyano-4-(3-methoxy-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid

The title compound is prepared from{(S)-6-[(R)-5-cyano-4-(3-methoxy-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester following a procedure analogous to that described forExample 1. LC (method 4): t_(R)=1.12 min; Mass spectrum(ESI^(+): m/z=)456 [M+H]⁺.

Example 4{(S)-6-[(R)-5-Cyano-4-(4-methoxy-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid

The title compound is prepared from{(S)-6-[(R)-5-cyano-4-(4-methoxy-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester following a procedure analogous to that described forExample 1. LC (method 4): t_(R)=1.12 min; Mass spectrum (ESI⁺): m/z=456[M+H]⁺.

Example 5{(S)-6-[(R)-5-Cyano-4-(2,6-dimethyl-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid

The title compound is prepared from{(S)-6-[(R)-5-cyano-4-(2,6-dimethyl-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester following a procedure analogous to that described forExample 1. LC (method 4): t_(R)=1.20 min; Mass spectrum (ESI⁻): m/z=452[M−H]⁻.

Example 6{(S)-6-[(R)-5-Cyano-4-(2-methyl-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid

The title compound is prepared from{(S)-6-[(R)-5-cyano-4-(2-methyl-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester following a procedure analogous to that described forExample 1. LC (method 4): t_(R)=1.16 min; Mass spectrum (ESI⁻): m/z=438[M−H]⁻.

Example 7{(S)-6-[(R)-5-Cyano-4-(4-methylsulfanyl-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid

The title compound is prepared from{(S)-6-[(R)-5-cyano-4-(4-methylsulfanyl-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester following a procedure analogous to that described forExample 1. LC (method 4): t_(R)=1.02 min; Mass spectrum (ESI⁻): m/z=470[M−H]⁻.

Example 8{(S)-6-[(R)-5-Cyano-4-(4-methylsulfonyl-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid

3-Chloroperoxybenzoic acid (26 mg) is added to a solution of{(S)-6-[(R)-5-cyano-4-(4-methylsulfanyl-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid (20 mg) in dichloromethane (1 mL) at room temperature. The mixtureis stirred at room temperature for 3 h and then concentrated. Theresidue is purified by HPLC on reversed phase (MeCN/water) to give thetitle compound. LC (method 4): t_(R)=1.01 min; Mass spectrum (ESI⁻):m/z=502 [M−H]⁻.

Example 9{(S)-6-[(R)-5-Cyano-4-(3-cyano-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid

The title compound is prepared from{(S)-6-[(R)-5-cyano-4-(3-cyano-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester following a procedure analogous to that described forExample 1. LC (method 4): t_(R)=1.08 min; Mass spectrum (ESI⁻): m/z=449[M−H]⁻.

Example 10{(S)-6-[(R)-4-Benzyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid

The title compound is prepared from{(S)-6-[(R)-4-benzyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester following a procedure analogous to that described forExample 1. LC (method 3): t_(R)=0.75 min; Mass spectrum (ESI⁻): m/z=467[M−H]⁻.

Example 11{(S)-6-[(R)-5-Cyano-4-(4-hydroxy-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid

The title compound is prepared from{(S)-6-[(R)-4-(4-acetoxy-benzyl)-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester following a procedure analogous to that described forExample 1. LC (method 4): t_(R)=1.16 min; Mass spectrum (ESI⁻): m/z=440[M−H]⁻.

Example 12{(S)-6-[(R)-5-Cyano-4-(4-methylsulfinyl-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid

Aqueous hydrogen peroxide (35%, 5 μL) is added to a solution of{(S)-6-[(R)-5-cyano-4-(4-methylsulfanyl-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid (120 mg) in 1,1,1,3,3,3-hexafluoro-2-propanol (1.5 mL) at roomtemperature. The mixture is stirred at room temperature for 2 h and thendiluted with ethyl acetate. The resulting mixture is washed with aqueousNa₂S₂C₃ solution, 1 M aqueous HCl solution, and brine, and dried(Na₂SO₄). The solvent is evaporated to give the title compound. LC(method 4): t_(R)=0.98 min; Mass spectrum (ESI⁺): m/z=488 [M+H]⁺.

Example 13{(S)-6-[(R)-7-Fluoro-4-(4-methoxybenzyl)-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}aceticacid

{(S)-6-[(R)-7-Fluoro-4-(4-methoxybenzyl)-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}aceticacid methyl ester (40.9 mg) is dissolved in tetrahydrofuran (4 mL) and1N aqueous sodium hydroxide solution (0.4 mL) is added. The mixture isstirred at room temperature overnight and then acidified with aqueous 1N hydrochloric acid (0.4 mL). The solution is submitted to HPLC onreversed phase (MeCN/water) to give the title compound. LC (method 6):t_(R)=0.71 min; Mass spectrum (ESI⁻): m/z=447 [M−H]⁻.

Example 14{(S)-6-[(R)-7-Fluoro-4-(3-methoxybenzyl)-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-aceticacid

{(S)-6-[(R)-7-Fluoro-4-(3-methoxybenzyl)-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-aceticacid methyl ester (30 mg) is dissolved in tetrahydrofuran (4 mL) and 1 Naqueous sodium hydroxide solution (0.4 mL) is added. The mixture isstirred at room temperature overnight and then acidified with 1 Naqueous hydrochloric acid (0.4 mL). The solution is submitted to HPLC onreversed phase (MeCN/water) to give the title compound. LC (method 6):t_(R)=0.71 min; Mass spectrum (ESI⁻): m/z=447 [M−H]⁻.

Example 15{(S)-6-[(R)-(6-Chloro-pyridin-3-ylmethyl)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid

{(S)-6-[(R)-(6-Chloro-pyridin-3-ylmethyl)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzo-furan-3-yl}-aceticacid methyl ester (18.6 mg) is dissolved in tetrahydrofuran (4 mL) and1N aqueous sodium hydroxide solution (0.4 mL) is added. The mixture isstirred at room temperature overnight and then acidified with 1N aqueoushydrochloric acid (0.4 mL). The solution is submitted to HPLC onreversed phase (MeCN/water) to give the title compound. LC (method 6):t_(R)=0.66 min; Mass spectrum (ESI⁻): m/z=452/454 (Cl) [M−H]⁻.

Example 16{(S)-6-[(R)-4-Benzyl-7-fluoro-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-aceticacid

{(S)-6-[(R)-4-Benzyl-7-fluoro-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-aceticacid methyl ester (18.6 mg) is dissolved in tetrahydrofuran (4 mL) and1N aqueous sodium hydroxide solution (0.4 mL) is added. The mixture isstirred at room temperature overnight and then acidified with 1N aqueoushydrochloric acid (0.4 mL). The solution is submitted to HPLC onreversed phase (MeCN/water) to give the title compound. LC (method 6):t_(R)=0.72 min; Mass spectrum (ESI⁻): m/z=417 [M−H]⁻.

Example 17{(S)-6-[(R)-4-(4-Methylsulfonyl-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid

The title compound is prepared from{(S)-6-[(R)-4-(4-methylsulfonyl-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester following a procedure analogous to that described forExample 1; after saponification of the ester the organic solvents areevaporated, water is added to the residue, and the resulting mixture isneutralized with 1N aqueous HCl solution. Upon stirring the aqueoussolution, the title compound precipitates from the solution, theprecipitate is collected and dried. LC (method 3): t_(R)=0.33 min; Massspectrum (ESI⁻): m/z=545 [M−H]⁻.

Example 18{(S)-6-[(R)-4-(3,5-Difluoro-benzyl)-7-fluoro-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-aceticacid

The title compound is prepared from{(S)-6-[(R)-4-(3,5-difluoro-benzyl)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester following a procedure analogous to that described forExample 1; after saponification of the ester the organic solvents areevaporated, water is added to the residue, and the resulting mixture isneutralized with 1N aqueous HCl solution. Upon stirring the aqueoussolution, the title compound precipitates from the solution, theprecipitate is collected and dried. LC (method 9): t_(R)=0.70 min; Massspectrum (ESI⁻): m/z=453 [M−H]⁻.

Example 19{(S)-6-[(R)-4-(2,6-Difluoro-benzyl)-7-fluoro-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-aceticacid

The title compound is prepared from{(S)-6-[(R)-4-(2,6-difluoro-benzyl)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester following a procedure analogous to that described forExample 1. LC (method 9): t_(R)=0.70 min; Mass spectrum (ESI⁻): m/z=453[M−H]⁻.

Example 20{(S)-6-[(R)-4-(4-Cyano-benzyl)-7-fluoro-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-aceticacid

The title compound is prepared from{(S)-6-[(R)-4-(4-cyano-benzyl)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester following a procedure analogous to that described forExample 1. LC (method 9): t_(R)=0.46 min; Mass spectrum (ESI⁻): m/z=442[M−H]⁻.

Example 21{(S)-6-[(R)-4-(2,4-Difluoro-benzyl)-7-fluoro-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-aceticacid

The title compound is prepared from{(S)-6-[(R)-4-(2,4-difluoro-benzyl)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester following a procedure analogous to that described forExample 1. LC (method 9): t_(R)=0.70 min; Mass spectrum (ESI⁻): m/z=453[M−H]⁻.

Example 22{(S)-6-[(R)-5-Cyano-4-(2-fluoro-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid

The title compound is prepared from{(S)-6-[(R)-5-cyano-4-(2-fluoro-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester following a procedure analogous to that described forExample 1; the crude product is purified by HPLC(acetonitrile/water/trifluoroacetic acid). LC (method 2): t_(R)=1.13min; Mass spectrum (ESI⁻): m/z=442 [M−H]⁻.

Example 23{(S)-6-[(R)-5-Cyano-4-(4-fluoro-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid

The title compound is prepared from{(S)-6-[(R)-5-cyano-4-(4-fluoro-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester following a procedure analogous to that described forExample 1; the crude product is purified by HPLC(acetonitrile/water/trifluoroacetic acid). LC (method 6): t_(R)=0.80min; Mass spectrum (ESI⁻): m/z=442 [M−H]⁻.

Example 24{(S)-6-[(R)-5-Cyano-4-(3-fluoro-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid

The title compound is prepared from{(S)-6-[(R)-5-cyano-4-(3-fluoro-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester following a procedure analogous to that described forExample 1; the crude product is purified by HPLC(acetonitrile/water/trifluoroacetic acid). LC (method 8): t_(R)=1.16min; Mass spectrum (ESI⁻): m/z=442 [M−H]⁻.

Example 25{(S)-6-[(R)-4-(4-Hydroxy-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-aceticacid

The title compound is prepared from{(S)-6-[(R)-4-(4-hydroxy-benzyl)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester following a procedure analogous to that described forExample 1; after saponification of the ester the organic solvents areevaporated, water is added to the residue, and the resulting mixture isneutralized with 1N aqueous HCl solution. Upon stirring the aqueoussolution, the title compound precipitates from the solution, theprecipitate is collected and dried. LC (method 8): t_(R)=1.14 min; Massspectrum (ESI⁻): m/z=483 [M−H]⁻.

Example 26{(S)-6-[(R)-4-(2,4-Difluoro-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-aceticacid

The title compound is prepared from{(S)-6-[(R)-4-(2,4-difluoro-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester following a procedure analogous to that described forExample 1; the crude product is purified by HPLC(acetonitrile/water/trifluoroacetic acid). LC (method 3): t_(R)=0.81min; Mass spectrum (ESI⁻): m/z=503 [M−H]⁻.

Example 27{(S)-6-[(R)-4-(3-Methoxy-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-aceticacid

The title compound is prepared from{(S)-6-[(R)-4-(3-methoxy-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester following a procedure analogous to that described forExample 1; after saponification of the ester the organic solvents areevaporated, water is added to the residue, and the resulting mixture isneutralized with 1N aqueous HCl solution. Upon stirring the aqueoussolution, the title compound precipitates from the solution, theprecipitate is collected and dried. LC (method 8): t_(R)=1.24 min; Massspectrum (ESI⁻): m/z=497 [M−H]⁻.

Example 28{(S)-6-[(R)-5-Cyano-4-(2,6-difluoro-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid

The title compound is prepared from{(S)-6-[(R)-5-cyano-4-(2,6-difluoro-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester following a procedure analogous to that described forExample 1. LC (method 4): t_(R)=1.15 min; Mass spectrum (ESI⁻): m/z=460[M−H]⁻.

Example 29{(S)-6-[(R)-4-(3-Fluoro-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-aceticacid

The title compound is prepared from{(S)-6-[(R)-4-(3-fluoro-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester following a procedure analogous to that described forExample 1; after saponification of the ester the organic solvents areevaporated, water is added to the residue, and the resulting mixture isneutralized with 1N aqueous HCl solution. Upon stirring the aqueoussolution, the title compound precipitates from the solution, theprecipitate is collected and dried. LC (method 8): t_(R)=1.26 min; Massspectrum (ESI⁻): m/z=485 [M−H]⁻.

Example 30{(S)-6-[(R)-4-(4-Fluoro-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-aceticacid

The title compound is prepared from{(S)-6-[(R)-4-(4-fluoro-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester following a procedure analogous to that described forExample 1; after saponification of the ester the organic solvents areevaporated, water is added to the residue, and the resulting mixture isneutralized with 1N aqueous HCl solution. Upon stirring the aqueoussolution, the title compound precipitates from the solution, theprecipitate is collected and dried. LC (method 6): t_(R)=0.88 min; Massspectrum (ESI⁻): m/z=485 [M−H]⁻.

Example 31{(S)-6-[(R)-4-(2-Fluoro-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-aceticacid

The title compound is prepared from{(S)-6-[(R)-4-(2-fluoro-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester following a procedure analogous to that described forExample 1; after saponification of the ester the organic solvents areevaporated, water is added to the residue, and the resulting mixture isneutralized with 1N aqueous HCl solution. Upon stirring the aqueoussolution, the title compound precipitates from the solution, theprecipitate is collected and dried. LC (method 6): t_(R)=0.89 min; Massspectrum (ESI⁻): m/z=485 [M−H]⁻.

Example 32{(S)-6-[(R)-5-Cyano-4-(2,3-difluoro-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid

The title compound is prepared from{(S)-6-[(R)-5-cyano-4-(2,3-difluoro-benzyl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester following a procedure analogous to that described forExample 1; the crude product is purified by HPLC(acetonitrile/water/trifluoroacetic acid). LC (method 4): t_(R)=1.16min; Mass spectrum (ESI⁻): m/z=460 [M−H]⁻.

Example 33{(S)-6-[(R)-4-(4-Methoxy-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-aceticacid

The title compound is prepared from{(S)-6-[(R)-4-(4-methoxy-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester following a procedure analogous to that described forExample 1; after saponification of the ester the organic solvents areevaporated, water is added to the residue, and the resulting mixture isneutralized with 1N aqueous HCl solution. Upon stirring the aqueoussolution, the title compound precipitates from the solution, theprecipitate is collected and dried. LC (method 6): t_(R)=0.89 min; Massspectrum (ESI⁻): m/z=497 [M−H]⁻.

Example 34{(S)-6-[(R)-4-(3-Cyano-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-aceticacid

The title compound is prepared from{(S)-6-[(R)-4-(3-cyano-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester following a procedure analogous to that described forExample 1; after saponification of the ester the organic solvents areevaporated, water is added to the residue, and the resulting mixture isneutralized with 1N aqueous HCl solution. Upon stirring the aqueoussolution, the title compound precipitates from the solution, theprecipitate is collected and dried. LC (method 6): t_(R)=0.85 min; Massspectrum (ESI⁻): m/z=492 [M−H]⁻.

Example 35{(S)-6-[(R)-4-(2-Methyl-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-aceticacid

The title compound is prepared from{(S)-6-[(R)-4-(2-methyl-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester following a procedure analogous to that described forExample 1; after saponification of the ester the organic solvents areevaporated, water is added to the residue, and the resulting mixture isneutralized with 1N aqueous HCl solution. Upon stirring the aqueoussolution, the title compound precipitates from the solution, theprecipitate is collected and dried. LC (method 6): t_(R)=0.91 min; Massspectrum (ESI⁻): m/z=481 [M−H]⁻.

Example 36{(S)-6-[(R)-4-(2-Cyano-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-aceticacid

The title compound is prepared from{(S)-6-[(R)-4-(2-cyano-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester following a procedure analogous to that described forExample 1; the crude product is purified by HPLC(acetonitrile/water/ammonia). LC (method 6): t_(R)=0.84 min; Massspectrum (ESI⁺): m/z=494 [M+H]⁺.

Example 37{(S)-6-[(R)-4-(4-Chloro-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-aceticacid

The title compound is prepared from{(S)-6-[(R)-4-(4-chloro-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester following a procedure analogous to that described forExample 1; the crude product is purified by HPLC(acetonitrile/water/trifluoroacetic acid). LC (method 3): t_(R)=0.89min; Mass spectrum (ESI⁻): m/z=501/503 (Cl) [M−H]⁻.

Example 38{(S)-6-[(R)-4-(2-Methoxy-pyridin-5-yl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-aceticacid

The title compound is prepared from{(S)-6-[(R)-4-(2-methoxy-pyridin-5-yl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester following a procedure analogous to that described forExample 1; the crude product is purified by HPLC(acetonitrile/water/trifluoroacetic acid). LC (method 2): t_(R)=1.13min; Mass spectrum (ESI⁺): m/z=500 [M+H]⁺.

Example 39{(S)-6-[(R)-4-(2-Fluoro-pyridin-5-yl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-aceticacid

The title compound is prepared from{(S)-6-[(R)-4-(2-fluoro-pyridin-5-yl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester following a procedure analogous to that described forExample 1; the crude product is purified by HPLC(acetonitrile/water/trifluoroacetic acid). LC (method 2): t_(R)=1.14min; Mass spectrum (ESI⁺): m/z=488 [M+H]⁺.

Example 40{(S)-6-[(R)-4-(2,5-Dimethoxy-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-aceticacid

The title compound is prepared from{(S)-6-[(R)-4-(2,5-dimethoxy-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-aceticacid methyl ester following a procedure analogous to that described forExample 1; after saponification of the ester the organic solvents areevaporated, water is added to the residue, and the resulting mixture isneutralized with 1N aqueous HCl solution. Upon stirring the aqueoussolution, the title compound precipitates from the solution, theprecipitate is collected and dried. LC (method 3): t_(R)=0.75 min; Massspectrum (ESI⁺): m/z=529 [M+H]⁺.

1. A compound of formula (I)

wherein: R¹ is selected from the group R¹-G1 consisting of phenyl-CH₂—and heteroaryl —CH₂—, wherein the phenyl ring and the heteroaryl ringthereof are optionally independently substituted with 1 to 5 R³ groups,and both —CH₂— moieties are optionally substituted with 1 or 2 H₃C—groups, wherein heteroaryl is a 5-membered heteroaromatic ring whichcontains 1 —NH— group, 1 —O—, or 1 —S— atom, or a 5-memberedheteroaromatic ring which contains 1 —NH—group, 1 —O— or —S— atom andadditionally 1 or 2 ═N— atoms, or a 6-membered heteroaromatic ring whichcontains 1, 2, or 3 ═N— atoms; R² is selected from the group R²-G1consisting of F, Cl, Br, NC—, F₂HC—, F₃C—, F₂HC—O—, and F₃C—O—; R³ isselected from the group R³-G1 consisting of F, Cl, Br, I, NC—, C₂N—,H₂N—, C₁₋₄-alkyl-NH—, (C₁₋₄-alkyl)₂N—, C₁₋₄-alkyl, C₂₋₄-alkenyl,C₂₋₄-alkinyl, HO—, HO—C₁₋₄-alkyl, C₁₋₄-alkyl-O—,C₁₋₄-alkyl-O—C₁₋₄-alkyl, C₁₋₄-alkyl-S—, C₁₋₄-alkyl-S(═O)—,C₁₋₄-alkyl-S(═O)₂—, C₃₋₆-cycloalkyl-, and C₃₋₆-cycloalkyl-O—, whereinany alkyl and cycloalkyl group or submoiety is optionally substitutedwith 1 to 5 fluorine atoms; and m is 1 or 2; wherein any alkyl group orsub-group is straight-chained or branched unless otherwise specified, ora salt thereof.
 2. The compound according to claim 1, wherein: R¹ isselected from the group R¹-G2 consisting of phenyl-CH₂— andheteroaryl-CH₂, wherein the phenyl ring is optionally independentlysubstituted with 1 to 5 R³ groups, the heteroaryl ring is optionallyindependently substituted with 1 to 3 groups R³ groups, and both —CH₂—moieties are optionally substituted with 1 or 2 H₃C— groups, and whereinheteroaryl is a 5-membered heteroaromatic ring which contains 1 —NH—group, 1 —O— or —S— atom and additionally 1 or 2 ═N— atoms, or a6-membered heteroaromatic ring which contains 1 or 2 ═N— atoms, or asalt thereof.
 3. The compound according to claim 1, wherein R² isselected from the group R²-G2 consisting of F, Cl, F₃C—, NC—, andF₃C—O—, or a salt thereof.
 4. The compound according to claim 1, whereinR³ is selected from the group R³-G2 consisting of F, Cl, Br, NC—,C₁₋₄-alkyl-NH—, (C₁₋₄-alkyl)₂N—, C₁₋₄-alkyl, F₂HC—, F₃C—, HO—,HO—C₁₋₄-alkyl, C₁₋₄-alkyl-O—, F₂HC—O—, F₃C—O—, C₁₋₄-alkyl-O—C₁₋₄-alkyl,C₁₋₄-alkyl-S—, C₁₋₄-alkyl-S(═O)—, C₁₋₄-alkyl-S(═O)₂—, C₃₋₆-cycloalkyl-,and C₃₋₆-cycloalkyl-O—, or a salt thereof.
 5. The compound according toclaim 1, wherein: R¹ is selected from the group R¹-G3 consisting of

wherein the phenyl group and each heteroaromatic group is optionallyindependently substituted with 1 to 3 R³ groups, and each —CH₂-moiety isoptionally substituted with 1 or 2 H₃C— groups; R² is selected from thegroup R²-G2 consisting of F, Cl, F₃C—, NC—, and F₃C—O—; R³ is selectedfrom the group R³-G3 consisting of F, Cl, NC—, C₁₋₄-alkyl, F₂HC—, F₃C—,HO—, HO—C₁₋₄-alkyl, F₂HC—O—, F₃C—O—, C₁₋₄-alkyl O—C₁₋₄-alkyl,C₁₋₄-alkyl-S—, C₁₋₄-alkyl-S(═O)—, C₁₋₄-alkyl-S(═O)₂—, C₃₋₆-cycloalkyl-,and C₄₋₆-cycloalkyl-O—; and m is 1 or 2, or a salt thereof.
 6. Thecompound according to claim 1, wherein: R¹ is selected from the groupR¹-G4a consisting of

wherein the phenyl group is optionally independently substituted with 1to 3 R³ groups, and the —CH₂— moiety is optionally substituted with 1 or2 H₃C— groups; R² is selected from the group R²-G3 consisting of F,F₃C—, and NC—; R³ is selected from the group R³-G3 consisting of F, Cl,NC—, C₁₋₄-alkyl, F₂HC—, F₃C—, HO—, HO—C₁₋₄-alkyl, F₂HC—O—, F₃C—O—,C₁₋₄-alkyl-O—C₁₋₄-alkyl, C₁₋₄-alkyl-S—, C₁₋₄-alkyl-S(═O)—,C₁₋₄-alkyl-S(═O)₂—, C₃₋₆-cycloalkyl-, and C₄₋₆-cycloalkyl-O—; and m is 1or 2, or a salt thereof.
 7. A pharmaceutically acceptable salt of thecompound according to claim
 1. 8. A pharmaceutical compositioncomprising the compound according to claim 1 or a pharmaceuticallyacceptable salt thereof, and an inert carrier or diluent.
 9. A methodfor treating diseases or conditions which can be influenced by themodulation of the function of GPR40, in a patient in need thereof,comprising administering a compound according to claim 1 or apharmaceutically acceptable salt thereof to the patient.
 10. (canceled)11. The method according to claim 9, wherein the treatment of diseasesor conditions which can be influenced by the modulation of the functionof GPR40 is diabetes and conditions associated with the disease,including insulin resistance, obesity, cardiovascular disease, anddyslipidemia.
 12. The pharmaceutical composition according to claim 8,further comprising an additional therapeutic agent.
 13. Thepharmaceutical composition according to claim 12, wherein the additionaltherapeutic agent is an antidiabetic agent, agent for the treatment ofoverweight and/or obesity, or an agent for the treatment of high bloodpressure, heart failure, and/or atherosclerosis.